Gastric Adenocarcinoma

MONDO:0005036 Pathograph 47 Show in embeddings browser gastric carcinoma adenocarcinoma

Gastric adenocarcinoma is a malignant gland-forming epithelial neoplasm arising from the glandular epithelium of the stomach. It is the dominant histology of gastric cancer (approximately 90% of cases) and a leading global cause of cancer death. It is not one disease mechanistically. Two largely distinct routes converge on the same organ: the intestinal-type Correa cascade, in which chronic Helicobacter pylori gastritis drives atrophic gastritis, intestinal metaplasia, dysplasia and finally invasive carcinoma; and the diffuse-type route, in which loss of the CDH1-encoded adherens-junction protein E-cadherin produces poorly cohesive, signet-ring-cell, infiltrative tumours that present younger and carry a worse prognosis. Superimposed on this histologic (Lauren) axis is the orthogonal TCGA molecular classification - Epstein-Barr-virus-positive, microsatellite-instable, genomically stable and chromosomally unstable - which carries the direct therapeutic implications. Modern management is biomarker-gated on HER2, PD-L1 CPS, MMR/MSI and claudin-18.2.

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Classifications

Harrison's Chapter

ICD-O Morphology

🔗

Mappings

MONDO

MONDO:0005036 gastric adenocarcinoma

This entry is scoped exactly to the MONDO gastric adenocarcinoma concept - the histologic parent of the existing H. pylori-associated, HER2-positive, EBV-associated and metastatic gastric entries, none of which carries this term.

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Inheritance

Sporadic (multifactorial)

The overwhelming majority of gastric adenocarcinoma is sporadic and multifactorial, driven by H. pylori infection, diet, smoking and age acting on a polygenic background. Roughly 10% shows familial clustering, and only about 1-3% is attributable to a recognised high-penetrance hereditary syndrome.

Show evidence (1 reference)

PMID:36483973 PARTIAL Human Clinical

"represents the main risk factor for the onset of gastric neoplasms"

Supports the sporadic/multifactorial framing: an acquired environmental exposure, not an inherited variant, is the main driver of gastric neoplasia. The precise 1-3% hereditary fraction is not quantified by this abstract, hence PARTIAL.

Autosomal dominant (hereditary syndromes) HP:0000006

The hereditary fraction is dominated by autosomal dominant syndromes: hereditary diffuse gastric cancer (CDH1, CTNNA1), Lynch syndrome (MLH1/MSH2/MSH6/PMS2), juvenile polyposis (SMAD4), familial adenomatous polyposis and gastric adenocarcinoma and proximal polyposis of the stomach (APC), Peutz-Jeghers syndrome (STK11) and Li-Fraumeni syndrome (TP53).

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:32758476 SUPPORT Human Clinical

"It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC."

Establishes the two autosomal dominant HDGC genes; HDGC is the archetype of the dominant hereditary route to gastric adenocarcinoma.

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Subtypes

histological lauren

Intestinal-type gastric adenocarcinoma (Lauren) MONDO:0005037

Gland-forming, well-to-moderately differentiated tumours arising through the Correa cascade of H. pylori gastritis, atrophy, intestinal metaplasia and dysplasia. Predominates in older men and in high-incidence regions, and is the histology most reduced by H. pylori eradication and endoscopic screening.

Show evidence (1 reference)

PMID:39023829 SUPPORT Human Clinical

"Approximately 90% of GC are adenocarcinomas (Ac), which are subdivided into diffuse and intestinal (Lauren classification)"

Guideline statement that the Lauren scheme splits gastric adenocarcinoma into intestinal and diffuse types, and that adenocarcinoma is ~90% of gastric cancer.

Diffuse-type gastric adenocarcinoma (Lauren) MONDO:0005017

CDH1 hgnc:1748 RHOA hgnc:667

Poorly cohesive tumours composed of individually infiltrating cells, frequently with signet-ring morphology, that spread within the gastric wall rather than forming a mass and may produce linitis plastica. Associated with E-cadherin (CDH1) loss, younger age at onset, peritoneal dissemination and worse prognosis than intestinal type.

Show evidence (1 reference)

PMID:24816255 SUPPORT Human Clinical

"Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction."

Characterises the infiltrative, stroma-inducing behaviour that defines the diffuse Lauren type.

Mixed-type gastric adenocarcinoma (Lauren)

Tumours containing both gland-forming intestinal and poorly cohesive diffuse components in appreciable proportion. Recognised as a third Lauren category; behaviour generally tracks the diffuse component. Included because the Lauren scheme is trichotomous, not binary - collapsing mixed tumours into one of the two poles loses the observation that the two programmes can coexist in one tumour.

Show evidence (1 reference)

PMID:24816255 PARTIAL Human Clinical

"the majority of which were histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa"

Direct histologic evidence that poorly differentiated (diffuse) and more differentiated (intestinal-like) components coexist within the same tumours - the observation the mixed Lauren category encodes. Support is PARTIAL because the paper describes the coexistence without using the "mixed type" label.

molecular tcga

Epstein-Barr virus-positive gastric adenocarcinoma (TCGA)

9% of the TCGA cohort (n=295)

Approximately 9% of gastric adenocarcinomas. Defined by clonal EBV infection of the tumour epithelium and characterised by recurrent PIK3CA mutation, extreme DNA hypermethylation, and amplification of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). The PD-L1/PD-L2 amplification makes this the molecular class with the clearest a priori rationale for checkpoint blockade. Curated in depth in the separate `EBV_Associated_Gastric_Cancer` entry.

Show evidence (2 references)

PMID:25079317 SUPPORT Human Clinical

"tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2)"

The TCGA definition of the EBV-positive molecular class, including the three features (PIK3CA, hypermethylation, PD-L1/L2 amplification) modelled as a pathophysiology node in this entry.

PMID:25079317 SUPPORT Human Clinical

"Tumours were first categorized by EBV-positivity (9%), then by MSI-high status, hereafter called MSI (22%), and the remaining tumours were distinguished by degree of aneuploidy into those termed genomically stable (20%) or those exhibiting chromosomal instability (CIN; 50%)."

Quantifies the EBV-positive class at 9% of the TCGA cohort, and gives the frequencies of all four molecular classes in one statement.

Microsatellite-instable gastric adenocarcinoma (TCGA)

22% of the TCGA cohort (n=295)

22% of the TCGA cohort. Tumours with mismatch-repair deficiency (most often sporadic MLH1 promoter hypermethylation, less often germline Lynch syndrome) producing elevated mutation rates and a hypermutated, neoantigen-rich genome. Strongly enriched for immunotherapy benefit and a mandatory biomarker test in advanced disease.

Show evidence (2 references)

PMID:25079317 SUPPORT Human Clinical

"microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins"

The TCGA definition of the MSI molecular class and its hypermutated phenotype.

PMID:25079317 SUPPORT Human Clinical

"then by MSI-high status, hereafter called MSI (22%)"

Quantifies the MSI class at 22% of the TCGA cohort.

Genomically stable gastric adenocarcinoma (TCGA)

20% of the TCGA cohort (n=295) RHOA hgnc:667 CLDN18 hgnc:2039

20% of the TCGA cohort. Tumours lacking both aneuploidy and hypermutation. Enriched for - but, importantly, not synonymous with - the diffuse Lauren histology, and characterised by RHOA mutation or CLDN18-ARHGAP fusion. This class is the clearest illustration of why the Lauren and TCGA axes must be kept separate: TCGA describes GS as enriched for the diffuse variant, an association rather than an identity.

Show evidence (3 references)

PMID:25079317 SUPPORT Human Clinical

"genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins"

Establishes both the molecular definition of the GS class and the fact that its relationship to diffuse histology is enrichment, not equivalence - the basis for keeping the Lauren and TCGA subtype axes distinct in this entry.

PMID:25079317 SUPPORT Human Clinical

"those termed genomically stable (20%)"

Quantifies the genomically stable class at 20% of the TCGA cohort.

PMID:25079317 SUPPORT Human Clinical

"CDH1 somatic mutations were enriched in the genomically stable subtype (37% of cases)."

Shows that somatic CDH1 inactivation - the sporadic counterpart of the germline HDGC lesion - concentrates in this class, linking the GS molecular class to the diffuse-route mechanism modelled in this entry.

Chromosomally unstable gastric adenocarcinoma (TCGA)

50% of the TCGA cohort (n=295) ERBB2 hgnc:3430 TP53 hgnc:11998

The largest molecular class, at 50% of the TCGA cohort. Marked aneuploidy with focal amplification of receptor tyrosine kinases (notably ERBB2/HER2, but also EGFR, MET, FGFR2), typically TP53 mutant, and enriched at the gastroesophageal junction and in intestinal histology. This is the class in which HER2-directed therapy is most often actionable.

Show evidence (3 references)

PMID:25079317 SUPPORT Human Clinical

"and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases"

The TCGA definition of the CIN class and its receptor-tyrosine-kinase amplification phenotype, which underpins HER2-directed therapy.

PMID:25079317 SUPPORT Human Clinical

"those exhibiting chromosomal instability (CIN; 50%)"

Quantifies CIN as the largest molecular class at 50% of the TCGA cohort.

PMID:25079317 SUPPORT Human Clinical

"Among the CIN tumours, we observed TP53 mutations in 71% of tumours."

Quantifies the near-universal TP53 mutation that permits the tolerated aneuploidy defining this class.

hereditary

Hereditary diffuse gastric cancer (germline CDH1/CTNNA1) MONDO:0007648

CDH1 hgnc:1748 CTNNA1 hgnc:2509 Autosomal dominant inheritance

Autosomal dominant syndrome caused by inactivating germline CDH1 variants, and in a minority of families CTNNA1, characterised by diffuse gastric cancer and lobular breast cancer. Distinct from the somatic diffuse-type subtype above because the first hit is constitutional in every gastric epithelial cell, which is what makes risk-reducing total gastrectomy a coherent - and recommended - intervention.

Show evidence (1 reference)

PMID:32758476 SUPPORT Human Clinical

"Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer."

IGCLC definition of HDGC, its inheritance mode and its two-tumour phenotype.

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Pathophysiology

Helicobacter pylori Chronic Active Gastritis

Persistent colonisation of the gastric mucosa by Helicobacter pylori establishes a lifelong, non-resolving active gastritis. The organism cannot be cleared by the host response it provokes, so the inflammatory stimulus is indefinite - exactly the persistent, non-resolving inflammatory driver pattern the tumor-promoting inflammation module abstracts, and which that module names H. pylori gastritis preceding gastric cancer as an archetype of. This is the initiating step of the Correa cascade and the dominant cause of non-cardia gastric adenocarcinoma.

gastric epithelial cell CL:0002178

inflammatory response GO:0006954 ↑ INCREASED

gastric mucosa UBERON:0001199

Downstream

CagA and VacA Virulence Factor Delivery Colonising cag-pathogenicity-island-positive strains inject effector proteins into the gastric epithelium.

Pro-Tumorigenic Gastric Inflammatory Microenvironment Persistent infection recruits and activates a myeloid-rich mucosal infiltrate.

Show evidence (2 references)

PMID:1458460 SUPPORT Human Clinical

"The initial stages of gastritis and atrophy have been linked to excessive salt intake and infection with Helicobacter pylori."

Correa's original formulation places H. pylori infection at the initiating gastritis stage of the cascade.

PMID:36483973 SUPPORT Human Clinical

"Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric environment of 60.3% of the world's population and represents the main risk factor for the onset of gastric neoplasms."

Establishes H. pylori as the principal risk factor for gastric neoplasia and the scale of the exposed population.

CagA and VacA Virulence Factor Delivery

Strains carrying the cag pathogenicity island use a type IV secretion system to translocate the CagA oncoprotein into gastric epithelial cells, where it is tyrosine phosphorylated and acts as a promiscuous pathological scaffold, simultaneously engaging multiple host signalling pathways and deranging proliferation, differentiation and apoptosis. The vacuolating cytotoxin VacA contributes independently to epithelial injury. Because transformation, once established, no longer requires the oncoprotein, CagA is described as acting by a hit-and-run mechanism - a mechanistically important caveat, since it means CagA positivity in an established tumour is not required for CagA to have caused it. Note the `protein tyrosine kinase activity` annotation on this node refers to the HOST kinases (SRC, ABL) that phosphorylate the translocated CagA EPIYA motifs; CagA itself is the substrate, not a kinase.

gastric epithelial cell CL:0002178

host SRC/ABL kinase activity phosphorylating CagA GO:0004713 ↑ INCREASED

Downstream

Pro-Tumorigenic Gastric Inflammatory Microenvironment CagA-driven epithelial signalling amplifies mucosal cytokine output.

Atrophic Gastritis and Achlorhydria Sustained epithelial injury and inflammation destroy oxyntic glands.

Show evidence (2 references)

PMID:36483973 SUPPORT Human Clinical

"CagA is the most important virulence factor in H. pylori, and is a translocated oncoprotein that induces morphofunctional modifications in gastric epithelial cells and a chronic inflammatory response that increases the risk of developing precancerous lesions."

Establishes CagA as a translocated oncoprotein linking infection to epithelial derangement and precancerous change.

PMID:36483973 SUPPORT In Vitro

"Upon translocation and tyrosine phosphorylation, CagA moves to the cell membrane and acts as a pathological scaffold protein that simultaneously interacts with multiple intracellular signaling pathways, thereby disrupting cell proliferation, differentiation and apoptosis."

Specifies the molecular mechanism (tyrosine phosphorylation, scaffold function) captured by this node's molecular_function annotation.

Pro-Tumorigenic Gastric Inflammatory Microenvironment

The chronically infected mucosa accumulates macrophages, neutrophils and lymphocytes that sustain cytokine production (IL-1beta, IL-6, TNF), NF-kB and STAT3 signalling, and mutagenic reactive oxygen and nitrogen species. This is the organ-specific instance of the module's pro-tumorigenic inflammatory microenvironment: it supplies both the proliferative/survival drive and the genotoxic stress that convert persistent gastritis into a field at risk of transformation.

macrophage CL:0000235 neutrophil CL:0000775

positive regulation of cytokine production GO:0001819 ↑ INCREASED

gastric mucosa UBERON:0001199

Downstream

Atrophic Gastritis and Achlorhydria Sustained inflammatory injury destroys oxyntic (acid-secreting) glands.

Show evidence (1 reference)

PMID:36483973 PARTIAL Human Clinical

"All these alterations in cell biology increase the risk of damaged cells acquiring pro-oncogenic genetic changes."

Links the CagA-driven inflammatory/epithelial derangement to acquisition of oncogenic genetic change, the output of this node. Support is PARTIAL: the review does not itemise the macrophage/neutrophil infiltrate or the specific IL-1beta/IL-6/TNF, NF-kB and STAT3 mediators named in the description, which are taken from the conserved module rather than from this source.

Atrophic Gastritis and Achlorhydria

Progressive loss of oxyntic glands (parietal and chief cells) produces multifocal atrophic gastritis with reduced or absent gastric acid secretion. Achlorhydria removes the stomach's principal antimicrobial barrier, permitting overgrowth of nitrate-reducing bacteria and altering the gastric microbiota, which in turn increases intragastric nitrosation and N-nitroso compound exposure. This is the step at which the mucosa commits to the metaplastic pathway.

gastric acid secretion GO:0001696 ↓ DECREASED

gastric mucosa UBERON:0001199

Downstream

Gastric Intestinal Metaplasia The atrophic, achlorhydric mucosa is replaced by intestinal-type epithelium.

Show evidence (1 reference)

PMID:1458460 PARTIAL Human Clinical

"The intermediate stages have been associated with the ingestion of ascorbic acid and nitrate, determinants of intragastric nitrosation."

Correa links the intermediate (atrophy/metaplasia) stages to intragastric nitrosation. Support is PARTIAL: the abstract places atrophy in the sequence and implicates nitrosation, but does not itself document achlorhydria, loss of the antimicrobial barrier, or nitrate-reducing bacterial overgrowth, which are asserted in the node description on textbook grounds.

Gastric Intestinal Metaplasia

The gastric mucosal epithelium is replaced by intestinal-type epithelium containing goblet and absorptive cells. Intestinal metaplasia is the defining precancerous lesion of the intestinal route and the point at which H. pylori eradication begins to lose its preventive efficacy - the mechanistic basis for the guideline emphasis on eradicating before advanced precancerous change.

gastric goblet cell CL:1000313

gastric mucosa UBERON:0001199

Downstream

Gastric Dysplasia Metaplastic epithelium accumulates further genetic and epigenetic hits and becomes cytologically and architecturally atypical.

Show evidence (1 reference)

PMID:1458460 SUPPORT Human Clinical

"Evidence from pathology and epidemiology studies has been provided for a human model of gastric carcinogenesis with the following sequential stages: chronic gastritis; atrophy; intestinal metaplasia; and dysplasia."

The canonical statement of the Correa cascade, placing intestinal metaplasia between atrophy and dysplasia.

Gastric Dysplasia

Unequivocally neoplastic but non-invasive epithelium confined by the basement membrane, graded low or high. High-grade dysplasia carries substantial short-term risk of progression and is the principal target of endoscopic surveillance and endoscopic resection. This node is also where the juvenile polyposis route enters the graph: germline SMAD4 loss produces gastric polyposis whose hamartomatous polyps are the substrate for dysplastic change and subsequent malignancy, a risk not shared by BMPR1A carriers.

SMAD4 hgnc:6770

gastric mucosa UBERON:0001199

Downstream

Intestinal-Type Invasive Adenocarcinoma Dysplastic epithelium breaches the basement membrane and invades the lamina propria and beyond.

Show evidence (1 reference)

PMID:1458460 SUPPORT Human Clinical

"chronic gastritis; atrophy; intestinal metaplasia; and dysplasia"

Places dysplasia as the terminal preinvasive stage of the Correa sequence.

Intestinal-Type Invasive Adenocarcinoma

Gland-forming carcinoma invading through the basement membrane into the lamina propria, submucosa and, in advanced disease, the muscularis propria and serosa. This is the terminal step of the Correa cascade and the histology most strongly coupled to the chromosomal-instability molecular class.

glandular epithelial cell of stomach CL:0002659

stomach UBERON:0000945

Downstream

Chromosomal Instability and Aneuploidy Intestinal-type tumours preferentially evolve along the aneuploid CIN trajectory.

Peritoneal Dissemination and Distant Metastasis Invasive carcinoma penetrates the serosa and disseminates.

Stomach cancer Invasive glandular carcinoma of the stomach is the defining neoplastic phenotype.

Epigastric pain Mucosal and mural involvement produces epigastric pain and dyspepsia.

Gastrointestinal hemorrhage Tumour ulceration erodes mucosal vessels, causing occult or overt bleeding.

Iron deficiency anemia Chronic occult blood loss from the ulcerated tumour depletes iron stores.

Dysphagia Proximal (cardia) tumours obstruct the gastric inlet and impair swallowing.

Show evidence (1 reference)

PMID:1458460 PARTIAL Human Clinical

Anchors the multistep human model leading up to this node. Support is PARTIAL because Correa's staged sequence terminates at dysplasia and does not itself assert the invasive-carcinoma endpoint.

CDH1 Inactivation and E-cadherin Loss

Biallelic inactivation of CDH1 abolishes E-cadherin, the transmembrane calcium-dependent adhesion molecule of the epithelial adherens junction. In hereditary diffuse gastric cancer the first hit is a germline truncating variant present in every gastric epithelial cell and the second hit is most often CDH1 promoter hypermethylation (or loss of heterozygosity, or somatic mutation); in sporadic diffuse cancer both hits are somatic. Germline CTNNA1 truncating variants produce the mechanistically equivalent lesion one step down the junction, by nonsense-mediated decay of the alpha-E-catenin transcript, but with lower penetrance.

CDH1 hgnc:1748

CDH1 hgnc:1748 CTNNA1 hgnc:2509

cell-cell adhesion GO:0098609 ↓ DECREASED

adherens junction GO:0005912

Downstream

Loss of Epithelial Cohesion and Signet Ring Cell Formation Without E-cadherin, epithelial cells fail to maintain junctional contacts and detach individually from the epithelial sheet.

Breast carcinoma The same adherens-junction lesion acts in breast epithelium, where E-cadherin loss produces the lobular breast carcinoma of hereditary diffuse gastric cancer.

Show evidence (2 references)

PMID:9537325 SUPPORT Human Clinical

"Sequencing of the E-cadherin gene revealed a G --> T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product."

The founding observation identifying a truncating germline E-cadherin (CDH1) variant as the cause of hereditary diffuse gastric cancer.

PMID:40998418 SUPPORT Human Clinical

"CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline CTNNA1-truncating carriers lose αE-catenin."

Establishes the loss-of-function mechanism for the CTNNA1 arm - NMD of truncating transcripts causing alpha-E-catenin loss at the same adherens junction.

Loss of Epithelial Cohesion and Signet Ring Cell Formation

Loss of E-cadherin releases cells from the epithelial sheet, disrupting apicobasal polarity, mitotic spindle orientation and anoikis control. Detached cells accumulate intracytoplasmic mucin that displaces the nucleus to the periphery, producing the signet-ring morphology. This node conforms to the module's EMT-activation node because E-cadherin loss is that node's canonical initiating lesion, but the conformance is deliberately scoped to the cadherin-loss / loss-of-adhesion arm only: diffuse gastric cancer loses E-cadherin structurally (mutation, promoter hypermethylation, LOH) rather than by SNAIL/SLUG/ZEB/TWIST-driven transcriptional repression, and does not execute a complete mesenchymal programme. The node therefore annotates only decreased cell-cell adhesion, NOT GO:0001837 epithelial to mesenchymal transition, which would overstate the biology.

gastric epithelial cell CL:0002178

cell-cell adhesion GO:0098609 ↓ DECREASED

Downstream

Diffuse Infiltrative Growth and Linitis Plastica Non-cohesive cells permeate the gastric wall singly and in small clusters rather than forming a discrete mass.

Show evidence (2 references)

PMID:9537325 SUPPORT Human Clinical

"Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas."

Ties reduced E-cadherin expression directly to the aggressive, poorly differentiated phenotype that this node models as loss of epithelial cohesion.

PMID:39379994 SUPPORT Human Clinical

"almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable"

Demonstrates that signet-ring-cell foci are the near-universal early cellular consequence of germline CDH1 loss, and that their progression is stochastic.

RHOA Gain-of-Function and CLDN18-ARHGAP Fusion

A quarter of diffuse gastric carcinomas carry recurrent gain-of-function RHOA hotspot mutations (Tyr42, Arg5, Gly17); others carry CLDN18-ARHGAP fusions that disable RHO-family GTPase-activating proteins. Both converge on deregulated RHO signalling, which sustains survival of non-adherent cells and drives the infiltrative, stroma-inducing phenotype. These lesions define the genomically stable TCGA class and are essentially absent from intestinal-type tumours.

RHOA hgnc:667

RHOA hgnc:667 CLDN18 hgnc:2039

GTPase activity GO:0003924 ⚠ ABNORMAL

Downstream

Diffuse Infiltrative Growth and Linitis Plastica Deregulated RHO signalling amplifies the infiltrative, stroma-inducing growth pattern.

Show evidence (2 references)

PMID:24816255 SUPPORT Human Clinical

"RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein."

Quantifies RHOA mutation frequency in diffuse gastric carcinoma and identifies the specific hotspot residues.

PMID:24816255 SUPPORT Human Clinical

"Several lines of functional evidence indicated that mutant RHOA works in a gain-of-function manner."

Establishes the gain-of-function (rather than loss-of-function) direction of the RHOA lesion asserted by this node.

Diffuse Infiltrative Growth and Linitis Plastica

Non-cohesive tumour cells permeate the gastric wall diffusely, provoking a dense desmoplastic stromal reaction. When the process is extensive the stomach becomes a rigid, thickened, non-distensible leather-bottle organ - linitis plastica. Because there is often no exophytic mass and the overlying mucosa can appear intact, endoscopic biopsy is falsely negative more often than in intestinal-type disease, contributing to late diagnosis and poor prognosis.

stomach UBERON:0000945

Downstream

Peritoneal Dissemination and Distant Metastasis Serosal penetration by non-cohesive cells seeds the peritoneal cavity, the characteristic route of spread for diffuse-type disease.

Stomach cancer Diffuse infiltrative carcinoma is the second route to the defining neoplastic phenotype.

Early satiety Transmural infiltration with desmoplasia stiffens the gastric wall and reduces compliance, limiting the volume tolerated per meal.

Weight loss Reduced gastric capacity and impaired intake drive progressive weight loss.

Show evidence (1 reference)

PMID:24816255 SUPPORT Human Clinical

"Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction."

Directly describes the infiltrative growth with stromal induction that constitutes this node.

Peritoneal Dissemination and Distant Metastasis

Both Lauren routes converge on dissemination. Transcoelomic spread after serosal penetration seeds the peritoneum and omentum (and, classically, the ovaries as Krukenberg tumours); lymphatic spread involves perigastric and distant nodes; and haematogenous spread reaches liver, lung and bone. Peritoneal carcinomatosis is the dominant and most treatment-refractory pattern in diffuse-type disease and defines incurability. Curated in depth in the separate `Metastatic_Gastric_Cancer` entry.

cell migration GO:0016477 ↑ INCREASED

peritoneum UBERON:0002358

Downstream

Tumor Immune Evasion and Checkpoint Engagement Disseminated tumour deposits persist by engaging inhibitory immune checkpoints.

Ascites Peritoneal carcinomatosis obstructs lymphatic drainage and exudes fluid, producing malignant ascites.

Weight loss Disseminated disease drives cancer cachexia with progressive weight loss.

Show evidence (1 reference)

PMID:39023829 SUPPORT Human Clinical

"Peritoneal metastases are present in almost 20% of GC at"

Quantifies peritoneal dissemination as present in almost 20% of gastric cancers already at diagnosis - direct support for transcoelomic spread as the dominant and clinically decisive metastatic route modelled by this node.

EBV-Driven Hypermethylation and Checkpoint Ligand Amplification

In roughly 9% of gastric adenocarcinomas, clonal Epstein-Barr virus infection of the tumour epithelium drives an extreme CpG island methylator phenotype that silences tumour-suppressor loci, together with recurrent PIK3CA mutation and amplification of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). The PD-L1/PD-L2 amplification is the mechanistically important part: it makes checkpoint ligand overexpression a structural genomic feature rather than an inducible response, which is the rationale for prioritising checkpoint blockade in this class. Loss of the SWI/SNF chromatin remodeller ARID1A (mutated in 55% of EBV-positive tumours) cooperates with the methylator phenotype in this epigenetic reprogramming, while TP53 mutation - dominant in the CIN class - is characteristically rare here.

PIK3CA hgnc:8975 CD274 hgnc:17635 ARID1A hgnc:11110

negative regulation of gene expression, epigenetic GO:0045814 ↑ INCREASED

Downstream

Tumor Immune Evasion and Checkpoint Engagement Amplified PD-L1/PD-L2 directly engages PD-1 on tumour-infiltrating T cells.

Show evidence (1 reference)

PMID:25079317 SUPPORT Human Clinical

TCGA defines all three features of this node - PIK3CA mutation, extreme hypermethylation, and PD-L1/PD-L2 amplification - in EBV-positive tumours.

Mismatch Repair Deficiency and Microsatellite Instability

Loss of DNA mismatch repair - usually by sporadic MLH1 promoter hypermethylation, less often by a germline Lynch syndrome variant - produces a hypermutated, microsatellite-unstable genome. The resulting frameshift neoantigen load makes these tumours the most immunotherapy-responsive gastric cancers. This conforms to the genome-instability module's mutator-phenotype node, which explicitly covers the hypermutated / microsatellite-unstable genome (MMR loss) manifestation.

MLH1 hgnc:7127 MSH2 hgnc:7325

mismatch repair GO:0006298 ↓ DECREASED

Downstream

Tumor Immune Evasion and Checkpoint Engagement Hypermutation generates abundant neoantigens, provoking a T-cell response that the tumour must then restrain via checkpoint engagement.

Show evidence (1 reference)

PMID:25079317 SUPPORT Human Clinical

"microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins"

TCGA characterisation of the MSI class as hypermutated with targetable consequences.

Chromosomal Instability and Aneuploidy

The genome-instability arm of the largest TCGA class. Near-universal TP53 mutation disables the checkpoint that would otherwise eliminate cells with missegregated chromosomes, permitting tolerated aneuploidy and widespread somatic copy-number alteration. Enriched in intestinal histology and at the gastroesophageal junction. This node is deliberately kept separate from the receptor-tyrosine-kinase amplification it enables, because the two are distinct mechanistic claims and only the latter is druggable - a drug that blocks HER2 does not correct chromosomal instability.

TP53 hgnc:11998

chromosome segregation GO:0007059 ⚠ ABNORMAL

Downstream

Receptor Tyrosine Kinase Amplification Copy-number instability generates the focal high-level amplifications of receptor tyrosine kinase loci that characterise this class.

Show evidence (2 references)

PMID:25079317 SUPPORT Human Clinical

"and tumours with chromosomal instability, which show marked aneuploidy"

TCGA definition of the aneuploidy that characterises the CIN class.

PMID:25079317 SUPPORT Human Clinical

"Among the CIN tumours, we observed TP53 mutations in 71% of tumours."

Quantifies the TP53 loss that permits the tolerated aneuploidy asserted here.

Receptor Tyrosine Kinase Amplification

Focal high-level amplification of receptor tyrosine kinase loci - ERBB2/HER2 most importantly, but also EGFR, MET and FGFR2 - generated by the underlying chromosomal instability. Unlike the aneuploidy that produces them, these amplifications are directly druggable, and this node is the actual molecular target of trastuzumab and of bemarituzumab. It is the mechanistic reason HER2, and now FGFR2b, testing is mandatory in advanced disease.

ERBB2 hgnc:3430 FGFR2 hgnc:3689

ERBB2 signaling pathway GO:0038128 ↑ INCREASED

Downstream

Peritoneal Dissemination and Distant Metastasis RTK-driven proliferation and survival support progression to disseminated disease.

Show evidence (2 references)

PMID:25079317 SUPPORT Human Clinical

"focal amplification of receptor tyrosine kinases"

TCGA identifies focal receptor-tyrosine-kinase amplification as the druggable feature of the chromosomally unstable class.

PMID:20728210 SUPPORT Human Clinical

"their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation"

Confirms HER2 amplification/overexpression as a measurable, therapeutically actionable lesion - the property that makes this node a therapeutic vulnerability.

Angiogenic Switch and VEGF-Driven Neovascularization

Growing gastric tumours outstrip their blood supply and switch to a pro-angiogenic phenotype, secreting VEGF-A that engages VEGFR2 (KDR) on tumour endothelium to drive neovascularization. This is the organ-specific instance of the tumour-angiogenesis module's central effector, and it is the target of the anti-VEGFR2 antibody ramucirumab, which is licensed second-line in advanced gastric adenocarcinoma.

VEGFA hgnc:12680 KDR hgnc:6307

angiogenesis GO:0001525 ↑ INCREASED vascular endothelial growth factor signaling pathway GO:0038084 ↑ INCREASED

Downstream

Peritoneal Dissemination and Distant Metastasis Tumour neovascularization sustains growth and provides the haematogenous route for dissemination.

Show evidence (2 references)

PMID:32861308 SUPPORT Human Clinical

"ramucirumab (anti-angiogenic second line)"

Establishes anti-angiogenic therapy as a licensed treatment class in gastric cancer, i.e. that VEGF-driven neovascularization is a validated, druggable node.

PMID:25240821 SUPPORT Human Clinical

"VEGFR-2 has a role in gastric cancer pathogenesis and progression."

States the role of VEGFR2 in gastric cancer pathogenesis, the premise of this node and of the ramucirumab indication built on it.

Tumor Immune Evasion and Checkpoint Engagement

Tumour and stromal PD-L1 expression - constitutive in EBV-amplified tumours, interferon-induced in the neoantigen-rich MSI class - engages PD-1 on tumour-infiltrating CD8-positive T cells and restrains their cytotoxic function. Quantified clinically as the PD-L1 combined positive score (CPS), this is the directly actionable node: blocking the PD-1/PD-L1 axis with pembrolizumab or nivolumab added to chemotherapy improves survival, with benefit concentrated at higher CPS and in MSI-high disease.

CD8-positive, alpha-beta T cell CL:0000625

CD274 hgnc:17635

negative regulation of T cell mediated immunity GO:0002710 ↑ INCREASED

Show evidence (2 references)

PMID:37875143 SUPPORT Human Clinical

"Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group."

Therapeutic proof that the PD-1/PD-L1 axis modelled by this node is a functional immune brake in gastric adenocarcinoma - blocking it improves survival.

PMID:39409957 SUPPORT Human Clinical

"it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI)"

Establishes PD-L1 CPS and MSI as mandatory decision biomarkers, i.e. that this node is clinically measured and acted upon.

✶

Histopathology

Intestinal Metaplasia of Gastric Mucosa

Replacement of gastric mucosal epithelium by intestinal-type epithelium with goblet cells. The defining precancerous lesion of the intestinal (Correa) route and the histologic finding that triggers endoscopic surveillance.

Show evidence (1 reference)

PMID:1458460 SUPPORT Human Clinical

"chronic gastritis; atrophy; intestinal metaplasia; and dysplasia"

Establishes intestinal metaplasia as a defined histologic stage of the human gastric carcinogenesis sequence.

Gastric Dysplasia

Unequivocally neoplastic non-invasive epithelium, graded low or high. High-grade dysplasia is the immediate precursor of invasive carcinoma and an indication for endoscopic resection.

Show evidence (1 reference)

PMID:1458460 SUPPORT Human Clinical

"with the following sequential stages: chronic gastritis; atrophy; intestinal metaplasia; and dysplasia"

Places dysplasia as the final preinvasive histologic stage of the Correa sequence.

Poorly Cohesive Growth Pattern

Malignant cells infiltrating singly or in tiny aggregates rather than forming glands - the architectural hallmark of diffuse-type (poorly cohesive) carcinoma in the current WHO scheme and the direct histologic readout of E-cadherin loss.

Show evidence (1 reference)

PMID:24816255 SUPPORT Human Clinical

"histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa"

Describes the poorly differentiated, non-gland-forming histology of the diffuse tumours in which RHOA mutations occur.

Signet Ring Cell Morphology VERY_FREQUENT

The characteristic cytology of the diffuse type: tumour cells distended by intracytoplasmic mucin that displaces the nucleus to the cell periphery, producing a signet-ring outline. Signet-ring foci are near-universal as pT1a lesions in prophylactic gastrectomy specimens from germline CDH1 carriers, where the behaviour of any individual focus is unpredictable.

Show evidence (1 reference)

PMID:39379994 SUPPORT Human Clinical

"almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC"

"Almost every" prophylactic total gastrectomy specimen maps to the VERY_FREQUENT band; the frequency is scoped to the HDGC subtype, where the quantitative claim was made, not to gastric adenocarcinoma overall.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 2

Gastrointestinal hemorrhage Gastrointestinal hemorrhage HP:0002239

Show evidence (1 reference)

PMID:39023829 PARTIAL Human Clinical

"particularly in the setting of ulcerated lesions"

Confirms that gastric adenocarcinoma commonly presents as an ulcerated lesion, the substrate for gastrointestinal haemorrhage.

Iron deficiency anemia Iron deficiency anemia HP:0001891

Clinical presenting features are textbook knowledge. No source in this entry's cited corpus states them in snippet-quotable form, so per CLAUDE.md SOP section 4 the claim is kept as description/notes rather than attached to a tangential quote.

Breast 1

Breast carcinoma Breast carcinoma HP:0003002

Show evidence (2 references)

PMID:32758476 SUPPORT Human Clinical

"Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer."

IGCLC guidelines establish lobular breast cancer as a defining component of the HDGC phenotype.

PMID:40998418 SUPPORT Human Clinical

"LBC is recurrent among CTNNA1-truncating carriers, some lacking HDGC criteria."

Extends the lobular breast cancer phenotype to the CTNNA1 arm, including carriers who do not meet classical HDGC criteria.

Digestive 4

Early satiety Early satiety HP:0033842

Dysphagia Dysphagia HP:0002015

Course: PROGRESSIVE

Ascites Ascites HP:0001541

Stomach cancer Stomach cancer HP:0012126

Show evidence (1 reference)

PMID:38572751 SUPPORT Human Clinical

"followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%)"

Establishes stomach cancer as a distinct, quantified disease entity in global cancer surveillance.

Growth 1

Weight loss Weight loss HP:0001824

Course: PROGRESSIVE

Other 1

Epigastric pain Epigastric pain HP:0410019

🧬

Genetic Associations

CDH1

Gene: CDH1 hgnc:1748 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:9537325 SUPPORT Human Clinical

"Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer in a large kindred from New Zealand (Aotearoa)."

The original identification of CDH1 as the hereditary diffuse gastric cancer gene.

PMID:40998418 SUPPORT Human Clinical

"Compared with wild-type individuals, GC risk is 7-fold higher in CTNNA1-truncating and 38-fold higher in CDH1-truncating variant carriers."

Quantifies the 38-fold gastric cancer risk of CDH1 truncating variants against population controls, and calibrates it against CTNNA1.

CTNNA1

Gene: CTNNA1 hgnc:2509 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:40998418 SUPPORT Human Clinical

"We demonstrate that compared with CDH1, CTNNA1 is a moderate penetrance HDGC gene."

The key calibration statement establishing CTNNA1 as moderate- rather than high-penetrance, which is what makes its management distinct from CDH1.

PMID:40998418 SUPPORT Human Clinical

"DGC risk is eightfold higher in truncating, compared with non-truncating carriers."

Establishes that only truncating CTNNA1 variants carry substantial diffuse gastric cancer risk - a variant-type distinction that matters for clinical reporting.

RHOA

Gene: RHOA hgnc:667 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:24816255 SUPPORT Human Clinical

"Comparison of mutational profiles for the major gastric cancer subtypes showed that RHOA mutations occur specifically in DGCs"

Establishes the histology specificity of RHOA mutation to diffuse gastric carcinoma, supporting its placement on the diffuse route only.

ERBB2

Gene: ERBB2 hgnc:3430 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:20728210 SUPPORT Human Clinical

"Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation."

Defines the HER2 overexpression/amplification lesion as a tumour-intrinsic, therapeutically actionable alteration in gastric adenocarcinoma.

FGFR2

Gene: FGFR2 hgnc:3689 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:36244398 SUPPORT Human Clinical

"910 patients were screened and 155 were randomly assigned to the bemarituzumab"

The 910-screened-to-155-enrolled ratio quantifies how small the FGFR2b-overexpressing subset of gastric adenocarcinoma is.

MLH1

Gene: MLH1 hgnc:7127 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:31337882 SUPPORT Human Clinical

"Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes"

Establishes MLH1 (with MSH2) as a high-penetrance dominant cancer-predisposition gene, the Lynch route into gastric adenocarcinoma.

MSH2

Gene: MSH2 hgnc:7325 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:31337882 SUPPORT Human Clinical

"older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate"

Prospective evidence that upper gastrointestinal (including gastric) cancer risk in Lynch syndrome is concentrated in older MSH2 carriers.

SMAD4

Gene: SMAD4 hgnc:6770 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:37400896 PARTIAL Human Clinical

"Unlike in SMAD4 carriers, gastric polyposis and malignancy were not identified in our review in BMPR1a carriers"

Establishes that within juvenile polyposis the gastric cancer risk is SMAD4-specific, preventing the common overstatement that juvenile polyposis as a whole confers gastric risk. Support is PARTIAL because this is a BMPR1A-focused study and the SMAD4 association is carried by the negative finding in its comparator arm rather than measured directly.

ARID1A

Gene: ARID1A hgnc:11110 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:25079317 SUPPORT Human Clinical

"EBV-positive tumours had frequent ARID1A (55%) and BCOR (23%) mutations and only rare TP53 mutations."

Quantifies ARID1A mutation in 55% of EBV-positive gastric adenocarcinomas and contrasts the near-absence of TP53 mutation in that class with its dominance in CIN.

PIK3CA

Gene: PIK3CA hgnc:8975 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:25079317 SUPPORT Human Clinical

"tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations"

TCGA identifies recurrent PIK3CA mutation as a defining feature of EBV-positive gastric adenocarcinoma.

TP53

Gene: TP53 hgnc:11998 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:25079317 SUPPORT Human Clinical

"Among the CIN tumours, we observed TP53 mutations in 71% of tumours."

Directly quantifies TP53 mutation in 71% of chromosomally unstable gastric adenocarcinomas, the permissive lesion for the tolerated aneuploidy that defines the class.

💊

Medical Actions

Prophylactic Total Gastrectomy for Germline CDH1 Carriers

Category: Therapeutic Action: Total Gastrectomy NCIT:C185240

The highest-stakes actionable recommendation in this entry. For carriers of a pathogenic germline CDH1 variant, risk-reducing total gastrectomy remains the IGCLC recommended option for gastric cancer risk management, and is the only intervention that substantially eliminates it (rare post-gastrectomy diffuse gastric cancer is reported from residual mucosa at the anastomosis). Threshold and timing: surgery is recommended in early adulthood, generally between 20 and 30 years of age, and is NOT recommended over age 70 unless there are significant mitigating circumstances. For carriers who decline or postpone, the IGCLC recommends annual endoscopy by endoscopists experienced in HDGC, and eradication of Helicobacter pylori if present. The 2020 IGCLC guidelines relaxed the genetic testing criteria (mainly by loosening age limits) and, critically, now express increasing confidence that endoscopic surveillance in expert centres can be safely offered to carriers who wish to postpone surgery or whose risk is not well defined - so the recommendation is no longer uniform. The reason the threshold has moved is quantitative: including less-selected families, the cumulative lifetime risk of advanced diffuse gastric cancer is now estimated at 13-19%, far below older high-risk-family estimates, while roughly a third of carriers decline surgery because of its lifelong physical and psychological consequences. Surveillance is imperfect: almost every prophylactic gastrectomy specimen already contains small pT1a signet-ring-cell foci of unpredictable behaviour, so the goal of endoscopic surveillance must be detecting atypical deeper-infiltrating lesions rather than every signet-ring focus. CTNNA1 carriers should not be managed by simple extrapolation from CDH1, being moderate-penetrance. Lifelong sequelae of total gastrectomy include small frequent meals, weight loss, dumping, reflux, and iron and vitamin B12 deficiency.

Mechanism Target:

INHIBITS CDH1 Inactivation and E-cadherin Loss — Removes the entire at-risk epithelial compartment in which the germline first hit is present, pre-empting the somatic second hit.

Show evidence (8 references)

PMID:32758476 SUPPORT Human Clinical

"Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers."

The core IGCLC recommendation curated here.

PMID:32758476 SUPPORT Human Clinical

"Where possible, surgery is recommended in early adulthood, generally between 20 and 30yrs of age."

The IGCLC age window for risk-reducing total gastrectomy - the timing threshold this treatment entry turns on.

PMID:32758476 SUPPORT Human Clinical

"PTG is not recommended in patients over 70yrs unless there are significant mitigating circumstances."

The upper age bound, driven by perioperative risk and prolonged recovery.

+ 5 more references

Curative Gastrectomy with D2 Lymphadenectomy

Category: Therapeutic Action: Gastrectomy NCIT:C15236

The definitive operation for non-early, operable gastric adenocarcinoma: subtotal or total gastrectomy with a D2 lymphadenectomy clearing the perigastric mesenteric and coeliac-branch nodal stations. Distinct from the prophylactic total gastrectomy offered to unaffected germline CDH1 carriers - this is resection of established cancer with curative intent, and is normally combined with perioperative chemotherapy.

Mechanism Target:

INHIBITS Intestinal-Type Invasive Adenocarcinoma — Removes the invasive primary tumour and its draining nodal basin before dissemination becomes established.

INHIBITS Diffuse Infiltrative Growth and Linitis Plastica — Resects transmurally infiltrating disease; total gastrectomy is usually required because diffuse tumours lack a discrete margin.

Show evidence (2 references)

PMID:32861308 SUPPORT Human Clinical

"Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches)."

Defines the standard curative operation and the required extent of lymphadenectomy.

PMID:32861308 SUPPORT Human Clinical

"Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers."

Establishes that surgery is combined with perioperative/adjuvant chemotherapy from stage 1B upward, linking this entry to the FLOT treatment.

Ramucirumab (Anti-VEGFR2) Second-Line Therapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: ramucirumab NCIT:C70792

Human IgG1 monoclonal antibody antagonist of VEGFR2 (KDR), licensed second line in advanced gastric and gastroesophageal junction adenocarcinoma, given with paclitaxel (RAINBOW) or as monotherapy (REGARD). It is the only anti-angiogenic agent with phase 3 survival benefit in this disease and, unlike the HER2, CLDN18.2, PD-L1 and FGFR2b agents, requires no predictive biomarker. Characteristic class toxicities are hypertension, proteinuria and bleeding.

Mechanism Target:

INHIBITS Angiogenic Switch and VEGF-Driven Neovascularization — Blocks VEGFR2 on tumour endothelium, cutting off the VEGF-driven neovascularization that sustains tumour growth.

Show evidence (2 references)

PMID:25240821 SUPPORT Human Clinical

"We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel."

Defines the agent, its molecular target and the second-line indication curated here.

PMID:32861308 SUPPORT Human Clinical

"Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line)."

Places ramucirumab in the licensed second-line position, alongside the other targeted agents curated in this entry.

Breast Surveillance for Female CDH1 Carriers

Category: Screening Action: Cancer Screening NCIT:C15406

Lobular breast cancer is the second tumour of hereditary diffuse gastric cancer, so gastric risk management alone is insufficient for female germline CDH1 carriers. The IGCLC offers annual breast surveillance as one of the two acceptable strategies for managing that risk (the other being risk-reducing mastectomy, curated separately below). Recorded as a distinct clinical action because it is co-equal in stakes with the gastric recommendation and is easily overlooked once prophylactic gastrectomy has been addressed.

Show evidence (1 reference)

PMID:32758476 SUPPORT Human Clinical

"LBC risk should be managed with either annual surveillance or bilateral risk-reducing mastectomy (BRRM)."

The IGCLC recommendation establishing annual surveillance as one of the two acceptable strategies for the breast arm of HDGC risk management.

Risk-Reducing Bilateral Mastectomy for Female CDH1 Carriers

Category: Therapeutic Action: Prophylactic Mastectomy NCIT:C94445

Bilateral risk-reducing mastectomy is the surgical alternative to annual breast surveillance for female germline CDH1 carriers, and is the breast counterpart of prophylactic total gastrectomy: it removes the at-risk epithelial compartment in which the germline first hit is present. Modelled as its own THERAPEUTIC/SURGERY treatment rather than folded into the surveillance entry, matching the existing pattern in `Hereditary_Breast_and_Ovarian_Cancer_Syndrome`, `Cowden_Syndrome` and `Li-Fraumeni_Syndrome`, so that a query for surgical prophylaxis in CDH1 carriers returns it.

Mechanism Target:

INHIBITS CDH1 Inactivation and E-cadherin Loss — Removes the at-risk breast epithelial compartment carrying the germline CDH1 first hit, pre-empting the somatic second hit that would produce lobular breast carcinoma.

Show evidence (1 reference)

PMID:32758476 SUPPORT Human Clinical

"LBC risk should be managed with either annual surveillance or bilateral risk-reducing mastectomy (BRRM)."

The IGCLC recommendation establishing bilateral risk-reducing mastectomy as the surgical option for the breast arm of HDGC risk management.

Perioperative FLOT Chemotherapy

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986 Regimen: FLOT regimen Ontology label: FLOT Regimen NCIT:C160565

Agent: fluorouracil CHEBI:46345 oxaliplatin CHEBI:31941 leucovorin CHEBI:15640 docetaxel CHEBI:4672

Fluorouracil, leucovorin, oxaliplatin and docetaxel given before and after gastrectomy for fit patients with locally advanced resectable gastric or gastroesophageal junction adenocarcinoma. Established as the Western standard by FLOT4, which reported a median overall survival of 50 months versus 35 months against the prior ECF/ECX standard (hazard ratio 0.77).

Show evidence (2 references)

PMID:30982686 SUPPORT Human Clinical

"Overall survival was increased in the FLOT group compared with the ECF/ECX group"

The FLOT4 primary result establishing perioperative FLOT as the standard of care.

PMID:30982686 SUPPORT Human Clinical

"In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX."

The authors' interpretation, defining the indication as curated here.

Trastuzumab for HER2-Positive Disease

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: trastuzumab NCIT:C1647

Anti-HER2 monoclonal antibody added to first-line fluoropyrimidine-platinum chemotherapy for HER2-overexpressing or HER2-amplified advanced gastric or gastroesophageal junction adenocarcinoma. The ToGA trial was the first demonstration that a targeted agent improves survival in this disease (median overall survival 13.8 versus 11.1 months). Trastuzumab deruxtecan is an important later-line option after trastuzumab exposure. See `HER2_Positive_Gastric_Cancer` for the deeper treatment curation.

Mechanism Target:

INHIBITS Receptor Tyrosine Kinase Amplification — Binds the amplified HER2 receptor, blocking its ERBB2 signalling output. Note the target is the RTK amplification node, not the upstream chromosomal instability - trastuzumab does not correct aneuploidy.

Show evidence (2 references)

PMID:20728210 SUPPORT Human Clinical

"Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046)."

The ToGA primary survival result quantifying HER2-directed benefit.

PMID:20728210 SUPPORT Human Clinical

"Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer."

Establishes the standard-of-care status of the HER2-directed indication.

Zolbetuximab for CLDN18.2-Positive HER2-Negative Disease

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: zolbetuximab NCIT:C85475

Chimeric IgG1 monoclonal antibody against claudin-18 isoform 2, added to mFOLFOX6 in the first line for CLDN18.2-positive, HER2-negative advanced disease. It kills CLDN18.2-expressing tumour cells by antibody- and complement-dependent cytotoxicity. The therapeutic window exists because normal CLDN18.2 expression is restricted to short-lived differentiated gastric mucosal epithelium. Nausea and vomiting are prominent infusion-related toxicities.

Show evidence (2 references)

PMID:37068504 SUPPORT Human Clinical

"Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6"

The SPOTLIGHT interpretation establishing efficacy on both progression-free and overall survival.

PMID:37068504 SUPPORT Human Clinical

"Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo"

Confirms the progression-free survival benefit of the CLDN18.2-directed indication.

PD-1 Checkpoint Blockade (Pembrolizumab, Nivolumab)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: pembrolizumab NCIT:C106432 nivolumab NCIT:C68814

Anti-PD-1 antibodies added to first-line chemotherapy for HER2-negative advanced disease, with eligibility gated on PD-L1 combined positive score and with the largest benefit in MSI-high/dMMR and high-CPS tumours. KEYNOTE-859 reported a significant overall survival improvement in the intention-to-treat population (12.9 versus 11.5 months, hazard ratio 0.78) that widened at higher CPS. Pembrolizumab is also added to trastuzumab plus chemotherapy in eligible PD-L1-positive HER2-positive disease. Immune-related adverse events are the characteristic toxicity class.

Mechanism Target:

INHIBITS Tumor Immune Evasion and Checkpoint Engagement — Blocks PD-1 on tumour-infiltrating T cells, releasing the checkpoint brake imposed by tumour PD-L1.

Show evidence (2 references)

PMID:37875143 SUPPORT Human Clinical

"Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population"

The KEYNOTE-859 primary overall survival result demonstrating checkpoint-blockade benefit.

PMID:37875143 SUPPORT Human Clinical

"pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma."

Defines the first-line HER2-negative indication curated here.

Bemarituzumab for FGFR2b-Overexpressing Disease

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: bemarituzumab NCIT:C120040

Afucosylated humanised monoclonal antibody against the FGFR2b isoform, added to mFOLFOX6 in FGFR2b-selected disease. The randomised phase 2 FIGHT study did not meet statistical significance for progression-free survival (9.5 versus 7.4 months, hazard ratio 0.68, p=0.073) but showed promising activity, and confirmatory phase 3 trials followed. Investigational rather than standard of care. A distinctive and dose-limiting on-target toxicity reported in the FIGHT safety analysis is corneal disorder, occurring as a grade 3 or worse event in 24% of bemarituzumab recipients and in none of the placebo group.

Mechanism Target:

INHIBITS Receptor Tyrosine Kinase Amplification — Blocks the FGFR2b receptor tyrosine kinase amplified/overexpressed in a subset of CIN-class tumours.

Show evidence (2 references)

PMID:36244398 PARTIAL Human Clinical

"median progression-free survival was 9·5 months (95% CI 7·3-12·9) in the bemarituzumab group and 7·4 months (5·8-8·4) in the placebo group"

Quantifies the efficacy signal. Support is PARTIAL because the difference did not reach statistical significance, which is why the entry frames bemarituzumab as investigational rather than standard of care.

PMID:36244398 SUPPORT Human Clinical

"In this exploratory phase 2 study, despite no statistically significant improvement in progression-free survival, treatment with bemarituzumab showed promising clinical efficacy."

The authors' own interpretation, which is the basis for the investigational framing and for the confirmatory phase 3 programme noted in the description.

Endoscopic Submucosal Dissection for Early Gastric Cancer

Category: Therapeutic Action: Endoscopic Submucosal Dissection NCIT:C157837

En-bloc endoscopic resection of selected superficial lesions confined to the mucosa with negligible nodal risk, achieving cure while preserving the stomach. Applies to early gastric cancer meeting size, depth, differentiation and ulceration criteria - essentially a Correa-route intervention, since it presupposes a discrete intestinal-type lesion rather than diffuse infiltration.

Mechanism Target:

INHIBITS Intestinal-Type Invasive Adenocarcinoma — Physically removes the intramucosal carcinoma before it can invade deeper or metastasise.

Show evidence (1 reference)

PMID:39023829 SUPPORT Human Clinical

"Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors"

Guideline statement placing endoscopic resection as the standard for very early stage disease.

Helicobacter pylori Screen-and-Treat (Primary Prevention)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Population-level detection and eradication of H. pylori, the leading supportable gastric cancer prevention strategy in intermediate- and high-incidence regions. Eradication is most effective before advanced atrophy and intestinal metaplasia develop - the mechanistic reason the intervention window is early in the Correa cascade. It also prevents peptic ulcer disease and gastric MALT lymphoma. A recognised trade-off is increased population antibiotic use. Note this treats the trigger; it does not treat established cancer.

Mechanism Target:

INHIBITS Helicobacter pylori Chronic Active Gastritis — Eliminates the persistent inflammatory stimulus that initiates the Correa cascade.

Show evidence (2 references)

PMID:39237127 SUPPORT Human Clinical

"the screen and treat strategy for Helicobacter pylori (H. pylori) seems to be the most appropriate for Europe"

Establishes H. pylori screen-and-treat as the leading population prevention strategy.

PMID:39237127 SUPPORT Human Clinical

"It has to be noted that increased use of antibiotics would be associated with this strategy."

Documents the antibiotic-stewardship trade-off of the strategy, curated as a caveat.

Endoscopic Surveillance in Hereditary and Precancerous Settings

Category: Screening Action: Gastroscopy NCIT:C16604

Upper endoscopy with protocol biopsies, used in two distinct settings: surveillance of advanced precancerous gastric conditions (extensive atrophic gastritis, intestinal metaplasia, dysplasia) along the Correa route, and as an alternative to immediate prophylactic gastrectomy for selected germline CDH1 carriers in expert centres. In the HDGC setting its sensitivity is inherently imperfect because signet-ring-cell foci are small, submucosal and endoscopically inapparent.

Show evidence (1 reference)

PMID:32758476 SUPPORT Human Clinical

"the growing capability of endoscopic and histological surveillance in HDGC"

IGCLC recognition of endoscopic and histological surveillance as an increasingly capable option in HDGC.

Genetic Counselling and Cascade Testing

Category: Counseling / Informational Action: Genetic Counseling NCIT:C15240

Referral for genetic counselling is indicated for young-onset diffuse gastric cancer, a family history meeting HDGC criteria, bilateral or familial lobular breast cancer, Lynch-compatible MSI, or polyposis. Testing should use a hereditary gastric cancer panel covering CDH1, CTNNA1, the mismatch repair genes, APC, STK11, SMAD4, BMPR1A and TP53, including deletion/duplication analysis. Identification of a familial variant triggers cascade testing of at-risk relatives, which is what converts a diagnosis in one patient into prevention for the family.

Show evidence (1 reference)

PMID:38160327 SUPPORT Human Clinical

"the guidelines offer detailed screening recommendations for hereditary gastric cancer"

Guideline confirmation that hereditary gastric cancer screening is a defined component of gastric cancer care.

🌍

Environmental Factors

Helicobacter pylori infection

The dominant modifiable cause and the main risk factor for gastric neoplasia, present in roughly 60% of the world's population. Widely cited attributable-fraction estimates put close to 90% of non-cardia gastric adenocarcinoma down to H. pylori, and IARC classifies it a Group 1 carcinogen; neither the 90% figure nor the IARC classification is snippet-quotable from the sources cited in this entry, so both are reported as context rather than as evidenced claims. Eradication reduces incidence, most effectively before advanced atrophy and metaplasia develop.

Show evidence (1 reference)

PMID:36483973 SUPPORT Human Clinical

"represents the main risk factor for the onset of gastric neoplasms"

Establishes H. pylori as the principal risk factor for gastric neoplasia.

High dietary salt and salt-preserved foods

High sodium intake and consumption of salt-preserved and nitrosated foods damage the gastric mucosa, potentiate H. pylori colonisation, and supply nitrosating precursors - contributing at both the initiating and the later stages of the Correa cascade.

Show evidence (1 reference)

PMID:1458460 SUPPORT Human Clinical

"The final stages have been linked with the supply of beta-carotene and with excessive salt intake."

Correa implicates excessive salt intake at the final stages of gastric carcinogenesis; the same abstract separately links the initial gastritis/atrophy stages to salt, quoted on the H. pylori gastritis node.

Tobacco smoking

An established risk factor for gastric adenocarcinoma at both cardia and non-cardia sites, acting independently of and additively with H. pylori infection.

Show evidence (1 reference)

PMID:38572751 PARTIAL Human Clinical

"targeting of key risk factors for cancer (including smoking, overweight and obesity, and infection)"

Indirect: GLOBOCAN names smoking and infection among the key modifiable cancer risk factors amenable to prevention. Gastric-specific risk magnitude is not quantified here.

🔬

Biochemical Markers

HER2 (ERBB2) Overexpression or Amplification

Show evidence (1 reference)

PMID:39409957 SUPPORT Human Clinical

"it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI)"

Establishes HER2 as one of the four essential biomarkers determining therapy selection in advanced gastric adenocarcinoma.

PD-L1 Combined Positive Score (CPS)

Show evidence (1 reference)

PMID:39023829 SUPPORT Human Clinical

"in tumor cells, lymphocytes, and macrophages relative to the total number of viable tumor cells, and is expressed as a score."

Defines exactly what the PD-L1 combined positive score counts, as curated here.

Mismatch Repair / Microsatellite Instability Status

Show evidence (1 reference)

PMID:38160327 SUPPORT Human Clinical

"updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients"

Guideline confirmation that dMMR/MSI-H status directs distinct management in gastric cancer.

Claudin-18.2 (CLDN18.2) Expression

Show evidence (1 reference)

PMID:37068504 SUPPORT Human Clinical

"CLDN18.2-positive (defined as ≥75% of tumour cells showing moderate-to-strong membranous CLDN18 staining)"

Gives the exact trial-validated CLDN18.2 positivity threshold curated here.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Gastric Adenocarcinoma:

Gastric MALT lymphoma MONDO:0007650

Overlapping Features The most important differential to keep mechanistically separate. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue shares H. pylori as its driver, arises in the same organ, and can look similar endoscopically - but it is a lymphoid, not epithelial, neoplasm with an entirely different natural history and first-line treatment. Curated separately as `MALT_Lymphoma`.

Distinguishing Features

Cell of origin is a marginal-zone B lymphocyte, not gastric glandular epithelium; immunohistochemistry (CD20-positive lymphoid infiltrate with lymphoepithelial lesions) separates them definitively.
Characteristic t(11;18)(q21;q21) API2-MALT1 translocation has no counterpart in gastric adenocarcinoma, and predicts failure of eradication therapy.
H. pylori eradication alone can induce durable remission in early-stage gastric MALT lymphoma; eradication never treats established gastric adenocarcinoma, in which it is a primary-prevention measure only.
Indolent course with prolonged survival, versus the aggressive course of adenocarcinoma.

Gastrointestinal stromal tumor MONDO:0011719

Overlapping Features Mesenchymal neoplasm of the interstitial cells of Cajal, the commonest gastric submucosal tumour. Presents as a submucosal mass with intact overlying mucosa, so superficial endoscopic biopsy is frequently non-diagnostic - the same pitfall as diffuse-type adenocarcinoma, but with a completely different answer. Curated separately as `Gastrointestinal_Stromal_Tumor`.

Distinguishing Features

KIT (CD117) and DOG1 positive, cytokeratin negative - the inverse of adenocarcinoma.
Driven by activating KIT or PDGFRA mutations and treated with imatinib; neither applies to adenocarcinoma.
Spindle or epithelioid mesenchymal morphology without gland formation or signet-ring cells.

Gastric neuroendocrine neoplasm Not Yet Curated MONDO:0003111

Overlapping Features Epithelial neoplasm of enterochromaffin-like cells. Type 1 lesions arise in autoimmune atrophic gastritis with hypergastrinaemia - the same atrophic background that predisposes to intestinal-type adenocarcinoma - so the two can coexist and must be distinguished on a single biopsy. Curated separately as `Gastroenteropancreatic_Neuroendocrine_Neoplasm`.

Distinguishing Features

Expresses chromogranin A and synaptophysin with organoid/trabecular architecture, unlike gland-forming adenocarcinoma.
Type 1 lesions are gastrin-driven, usually multiple, small and indolent, and are managed by surveillance or endoscopic resection rather than gastrectomy.
Graded by Ki-67 index and mitotic count (WHO neuroendocrine grading), not by Lauren type.

Gastroesophageal junction adenocarcinoma Not Yet Curated MONDO:0003219

Overlapping Features Adenocarcinoma centred at the gastroesophageal junction. Deliberately modelled as a differential rather than a subtype: junctional tumours share systemic-therapy evidence with gastric adenocarcinoma (they were co-enrolled in ToGA, FLOT4, SPOTLIGHT and FIGHT) but differ in aetiology, being driven by obesity and reflux rather than H. pylori, and overlapping the Barrett-derived esophageal adenocarcinoma biology curated in `Esophageal_Adenocarcinoma`.

Distinguishing Features

Anatomic epicentre at the junction (Siewert classification) rather than in the gastric body or antrum.
Aetiologically linked to gastroesophageal reflux, Barrett metaplasia and obesity, not to H. pylori-driven atrophic gastritis.
Higher HER2 positivity rate than distal gastric tumours, and different locoregional management (chemoradiation has a defined role at the junction).

Show evidence (1 reference)

PMID:39409957 SUPPORT Human Clinical

"To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction"

Confirms that junctional adenocarcinoma is handled alongside, but named separately from, gastric adenocarcinoma in systemic-therapy guidance - exactly the boundary modelled here.

Benign gastric ulcer MONDO:0001126

Overlapping Features Peptic ulceration, most often H. pylori- or NSAID-related. Endoscopically an ulcerated gastric adenocarcinoma can be indistinguishable from a benign ulcer, which is why guidelines mandate biopsy of every gastric ulcer and endoscopic confirmation of healing. Curated separately as `Gastric_Ulcer`.

Distinguishing Features

Histology shows inflammation, granulation tissue and regenerative change without invasive malignant epithelium.
Benign ulcers heal completely on acid suppression and H. pylori eradication; persistent or non-healing ulceration mandates re-biopsy for malignancy.
Regular ulcer margins with radiating folds, versus the heaped, irregular, indurated margins of a malignant ulcer.

Show evidence (1 reference)

PMID:39023829 SUPPORT Human Clinical

"particularly in the setting of ulcerated lesions"

The guideline singles out ulcerated lesions as requiring extra biopsy sampling, reflecting the difficulty of separating malignant from benign gastric ulceration.

📊

Related Datasets

https://portal.gdc.cancer.gov/projects/TCGA-STAD https://portal.gdc.cancer.gov/projects/TCGA-STAD

The Cancer Genome Atlas stomach adenocarcinoma project (TCGA-STAD). Multi-platform molecular profiling (whole-exome sequencing, mRNA and miRNA expression, DNA methylation, copy number and reverse-phase protein arrays) of 295 primary gastric adenocarcinomas. This is the dataset from which the four-class EBV / MSI / genomically stable / chromosomal instability molecular taxonomy used throughout this entry was derived, and the primary resource for validating those class assignments.

human MULTI OMICS n=295

PMID:25079317

Show evidence (1 reference)

PMID:25079317 SUPPORT Human Clinical

"Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project."

Establishes the dataset's identity, size (295 primary tumours) and multi-platform molecular scope.

{ }

Source YAML

click to show

name: Gastric Adenocarcinoma
creation_date: "2026-08-01T07:20:00Z"
description: >-
  Gastric adenocarcinoma is a malignant gland-forming epithelial neoplasm arising from
  the glandular epithelium of the stomach. It is the dominant histology of gastric
  cancer (approximately 90% of cases) and a leading global cause of cancer death.
  It is not one disease mechanistically. Two largely distinct routes converge on the
  same organ: the intestinal-type Correa cascade, in which chronic Helicobacter pylori
  gastritis drives atrophic gastritis, intestinal metaplasia, dysplasia and finally
  invasive carcinoma; and the diffuse-type route, in which loss of the CDH1-encoded
  adherens-junction protein E-cadherin produces poorly cohesive, signet-ring-cell,
  infiltrative tumours that present younger and carry a worse prognosis. Superimposed
  on this histologic (Lauren) axis is the orthogonal TCGA molecular classification -
  Epstein-Barr-virus-positive, microsatellite-instable, genomically stable and
  chromosomally unstable - which carries the direct therapeutic implications. Modern
  management is biomarker-gated on HER2, PD-L1 CPS, MMR/MSI and claudin-18.2.
categories:
- Gastrointestinal Cancer
- Gastric Cancer
- Adenocarcinoma
- Solid Tumor
parents:
- gastric carcinoma
- adenocarcinoma
synonyms:
- stomach adenocarcinoma
- adenocarcinoma of the stomach
- gastric (stomach) adenocarcinoma
- STAD
disease_term:
  preferred_term: gastric adenocarcinoma
  term:
    id: MONDO:0005036
    label: gastric adenocarcinoma

notes: >-
  Scope and boundaries with neighbouring dismech entries. This entry is the histologic
  parent concept (MONDO:0005036) and is deliberately kept distinct from four existing
  aspect-specific gastric entries, none of which carries MONDO:0005036:
  `Gastric_Cancer_H_pylori_Associated` (the infectious-etiology view),
  `HER2_Positive_Gastric_Cancer` (a biomarker-defined therapeutic subset),
  `EBV_Associated_Gastric_Cancer` (one TCGA molecular class curated in depth), and
  `Metastatic_Gastric_Cancer` (the advanced-stage view, MONDO:0004950). This entry
  models the shared mechanism graph and the two Lauren routes.

  LUMP/SPLIT CAVEAT REQUIRING HUMAN ADJUDICATION (@cmungall). There IS real mechanistic
  overlap with `Gastric_Cancer_H_pylori_Associated`, which already models CagA
  signalling, VacA injury, the Correa cascade, atrophic gastritis, intestinal metaplasia
  and CDH1/E-cadherin loss. Route A of this entry re-derives much of that chain. The
  case for this entry is that MONDO:0005036 was unclaimed, and that the TCGA molecular
  axis, the HDGC arm and the modern biomarker-gated therapeutic axis are genuinely new.
  But the alternative resolution - trimming the aspect-specific entries and redirecting
  them here - is equally defensible and should be decided by a human curator rather than
  unilaterally.

  Gastric MALT lymphoma is NOT a variant of gastric adenocarcinoma. Both are driven by
  chronic H. pylori infection, but MALT lymphoma is a B-cell lymphoma of
  mucosa-associated lymphoid tissue (`MALT_Lymphoma`, MONDO:0007650) with a distinct
  cell of origin, distinct genetics (t(11;18) API2-MALT1) and a distinct primary
  treatment (H. pylori eradication alone can induce remission). It is modelled here
  only as a differential diagnosis.

  Gastroesophageal junction (GEJ) adenocarcinoma is a deliberate boundary case. Most of
  the pivotal systemic-therapy trials cited here (ToGA, FLOT4, SPOTLIGHT, KEYNOTE-859,
  FIGHT) enrolled gastric AND GEJ adenocarcinoma together, so the treatment evidence is
  quoted as the trials framed it rather than being silently narrowed to pure gastric
  disease. Mechanistically, however, distal/non-cardia gastric adenocarcinoma is
  H. pylori-driven whereas GEJ and cardia tumours track with obesity and reflux and
  overlap the Barrett-derived biology curated in `Esophageal_Adenocarcinoma`. GEJ
  adenocarcinoma has its own MONDO term (MONDO:0003219) and is treated here as a
  differential diagnosis, not a subtype.

  The Lauren axis and the TCGA axis are NOT interchangeable and must not be collapsed
  into a single subtype list. They are cross-cutting: the genomically stable (GS)
  molecular class is *enriched for* - but not equivalent to - diffuse histology, and
  EBV-positive, MSI and CIN tumours each span multiple Lauren types. `has_subtypes`
  therefore carries both axes with distinct `classification` values
  (`histological_lauren` vs `molecular_tcga`), plus a separate `hereditary` axis.

  Ontology gaps encountered during curation (worth reporting upstream). (1) NCIT:C3190 "Linitis Plastica" exists but sits
  under "Finding by Site or System", not under the histopathology branch, so it is not
  bindable as a `finding_term`; linitis plastica is instead captured in the
  "Diffuse Infiltrative Growth and Linitis Plastica" pathophysiology node. Arguably
  correct, since linitis plastica is a macroscopic rather than microscopic finding.
  (The HPO term HP:0020168 "Tumor signet ring cell" is likewise outside the
  `HistopathologyFindingTerm` reachable set, but NCIT:C5250 "Gastric Signet Ring Cell
  Adenocarcinoma" IS reachable via NCIT:C4741 and is used here, so signet-ring cytology
  is not a gap.) (2) Five subtypes carry no `subtype_term` because MONDO has no corresponding class:
  mixed-type gastric adenocarcinoma, and all four TCGA molecular classes (EBV-positive,
  MSI, genomically stable, chromosomal instability). This is a real MONDO gap rather
  than a curation omission - the `test_subtypes_have_disease_term` warning on this file
  is therefore expected. The Intestinal, Diffuse and HDGC subtypes are all bound.

references:
- reference: PMID:25079317
  title: "Comprehensive molecular characterization of gastric adenocarcinoma."
- reference: PMID:32758476
  title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."

prevalence:
- population: Worldwide
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: UNKNOWN
  rate_per_100000: 11.5
  notes: >-
    GLOBOCAN 2022 places stomach cancer at 4.9% of all incident cancers worldwide
    (roughly 970,000 new cases against ~20 million total), i.e. an order of
    magnitude near 11-12 per 100,000 person-years crude. `prevalence_class` is left
    UNKNOWN rather than given an Orphanet band, because the Orphanet bands are
    point-prevalence classes and must not be applied to an annual-incidence rate.
    Adenocarcinoma accounts
    for approximately 90% of these. Incidence is strongly geographically
    concentrated (East Asia, Eastern Europe, Latin America) and is roughly
    twice as high in men, so the worldwide figure should not be applied locally.
  evidence:
  - reference: PMID:38572751
    reference_title: "Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%)"
    explanation: >-
      GLOBOCAN 2022 ranks stomach cancer fifth worldwide at 4.9% of all incident
      cancers, anchoring the global incidence estimate.

progression:
- phase: Advanced and metastatic disease
  notes: >-
    Stomach cancer is the fifth leading cause of cancer death worldwide, at 6.8% of all
    cancer deaths in 2022 - a mortality share larger than its 4.9% incidence share,
    reflecting late presentation and poor survival. Median survival in advanced disease
    remains under one year with sequential chemotherapy. Stage is the dominant
    predictor: completely resected early mucosal cancers can be cured, while metastatic
    disease is usually incurable.
  evidence:
  - reference: PMID:38572751
    reference_title: "Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by colorectal (9.3%), liver (7.8%), female breast (6.9%), and stomach (6.8%) cancers"
    explanation: >-
      Establishes stomach cancer's share of global cancer mortality, larger than its
      share of incidence.
  - reference: PMID:32861308
    reference_title: "Gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year."
    explanation: >-
      Quantifies the poor prognosis of advanced disease that drives the mortality burden.

has_subtypes:
# ---------------- Lauren histological axis ----------------
- name: Intestinal
  display_name: Intestinal-type gastric adenocarcinoma (Lauren)
  classification: histological_lauren
  description: >-
    Gland-forming, well-to-moderately differentiated tumours arising through the
    Correa cascade of H. pylori gastritis, atrophy, intestinal metaplasia and
    dysplasia. Predominates in older men and in high-incidence regions, and is the
    histology most reduced by H. pylori eradication and endoscopic screening.
  subtype_term:
    preferred_term: gastric intestinal type adenocarcinoma
    term:
      id: MONDO:0005037
      label: gastric intestinal type adenocarcinoma
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 90% of GC are adenocarcinomas (Ac), which are subdivided into diffuse and intestinal (Lauren classification)"
    explanation: >-
      Guideline statement that the Lauren scheme splits gastric adenocarcinoma into
      intestinal and diffuse types, and that adenocarcinoma is ~90% of gastric cancer.
- name: Diffuse
  display_name: Diffuse-type gastric adenocarcinoma (Lauren)
  classification: histological_lauren
  description: >-
    Poorly cohesive tumours composed of individually infiltrating cells, frequently
    with signet-ring morphology, that spread within the gastric wall rather than
    forming a mass and may produce linitis plastica. Associated with E-cadherin
    (CDH1) loss, younger age at onset, peritoneal dissemination and worse prognosis
    than intestinal type.
  subtype_term:
    preferred_term: diffuse gastric adenocarcinoma
    term:
      id: MONDO:0005017
      label: diffuse gastric adenocarcinoma
  genes:
  - preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  - preferred_term: RHOA
    term:
      id: hgnc:667
      label: RHOA
  evidence:
  - reference: PMID:24816255
    reference_title: "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction."
    explanation: >-
      Characterises the infiltrative, stroma-inducing behaviour that defines the
      diffuse Lauren type.
- name: Mixed
  display_name: Mixed-type gastric adenocarcinoma (Lauren)
  classification: histological_lauren
  description: >-
    Tumours containing both gland-forming intestinal and poorly cohesive diffuse
    components in appreciable proportion. Recognised as a third Lauren category;
    behaviour generally tracks the diffuse component. Included because the Lauren
    scheme is trichotomous, not binary - collapsing mixed tumours into one of the
    two poles loses the observation that the two programmes can coexist in one tumour.
  evidence:
  - reference: PMID:24816255
    reference_title: "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "the majority of which were histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa"
    explanation: >-
      Direct histologic evidence that poorly differentiated (diffuse) and more
      differentiated (intestinal-like) components coexist within the same tumours -
      the observation the mixed Lauren category encodes. Support is PARTIAL because
      the paper describes the coexistence without using the "mixed type" label.
# ---------------- TCGA molecular axis ----------------
- name: EBV-positive
  subtype_frequency: 9% of the TCGA cohort (n=295)
  display_name: Epstein-Barr virus-positive gastric adenocarcinoma (TCGA)
  classification: molecular_tcga
  description: >-
    Approximately 9% of gastric adenocarcinomas. Defined by clonal EBV infection of
    the tumour epithelium and characterised by recurrent PIK3CA mutation, extreme DNA
    hypermethylation, and amplification of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2).
    The PD-L1/PD-L2 amplification makes this the molecular class with the clearest a
    priori rationale for checkpoint blockade. Curated in depth in the separate
    `EBV_Associated_Gastric_Cancer` entry.
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2)"
    explanation: >-
      The TCGA definition of the EBV-positive molecular class, including the three
      features (PIK3CA, hypermethylation, PD-L1/L2 amplification) modelled as a
      pathophysiology node in this entry.
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumours were first categorized by EBV-positivity (9%), then by MSI-high status, hereafter called MSI (22%), and the remaining tumours were distinguished by degree of aneuploidy into those termed genomically stable (20%) or those exhibiting chromosomal instability (CIN; 50%)."
    explanation: >-
      Quantifies the EBV-positive class at 9% of the TCGA cohort, and gives the
      frequencies of all four molecular classes in one statement.
- name: MSI
  subtype_frequency: 22% of the TCGA cohort (n=295)
  display_name: Microsatellite-instable gastric adenocarcinoma (TCGA)
  classification: molecular_tcga
  description: >-
    22% of the TCGA cohort. Tumours with mismatch-repair deficiency (most often sporadic MLH1 promoter
    hypermethylation, less often germline Lynch syndrome) producing elevated mutation
    rates and a hypermutated, neoantigen-rich genome. Strongly enriched for
    immunotherapy benefit and a mandatory biomarker test in advanced disease.
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins"
    explanation: >-
      The TCGA definition of the MSI molecular class and its hypermutated phenotype.
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "then by MSI-high status, hereafter called MSI (22%)"
    explanation: >-
      Quantifies the MSI class at 22% of the TCGA cohort.
- name: GS
  subtype_frequency: 20% of the TCGA cohort (n=295)
  display_name: Genomically stable gastric adenocarcinoma (TCGA)
  classification: molecular_tcga
  description: >-
    20% of the TCGA cohort. Tumours lacking both aneuploidy and hypermutation. Enriched for - but, importantly,
    not synonymous with - the diffuse Lauren histology, and characterised by RHOA
    mutation or CLDN18-ARHGAP fusion. This class is the clearest illustration of why
    the Lauren and TCGA axes must be kept separate: TCGA describes GS as enriched for
    the diffuse variant, an association rather than an identity.
  genes:
  - preferred_term: RHOA
    term:
      id: hgnc:667
      label: RHOA
  - preferred_term: CLDN18
    term:
      id: hgnc:2039
      label: CLDN18
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins"
    explanation: >-
      Establishes both the molecular definition of the GS class and the fact that its
      relationship to diffuse histology is enrichment, not equivalence - the basis for
      keeping the Lauren and TCGA subtype axes distinct in this entry.
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "those termed genomically stable (20%)"
    explanation: >-
      Quantifies the genomically stable class at 20% of the TCGA cohort.
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CDH1 somatic mutations were enriched in the genomically stable subtype (37% of cases)."
    explanation: >-
      Shows that somatic CDH1 inactivation - the sporadic counterpart of the germline
      HDGC lesion - concentrates in this class, linking the GS molecular class to the
      diffuse-route mechanism modelled in this entry.
- name: CIN
  subtype_frequency: 50% of the TCGA cohort (n=295)
  display_name: Chromosomally unstable gastric adenocarcinoma (TCGA)
  classification: molecular_tcga
  description: >-
    The largest molecular class, at 50% of the TCGA cohort. Marked aneuploidy with focal amplification of receptor
    tyrosine kinases (notably ERBB2/HER2, but also EGFR, MET, FGFR2), typically TP53
    mutant, and enriched at the gastroesophageal junction and in intestinal histology.
    This is the class in which HER2-directed therapy is most often actionable.
  genes:
  - preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases"
    explanation: >-
      The TCGA definition of the CIN class and its receptor-tyrosine-kinase
      amplification phenotype, which underpins HER2-directed therapy.
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "those exhibiting chromosomal instability (CIN; 50%)"
    explanation: >-
      Quantifies CIN as the largest molecular class at 50% of the TCGA cohort.
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the CIN tumours, we observed TP53 mutations in 71% of tumours."
    explanation: >-
      Quantifies the near-universal TP53 mutation that permits the tolerated aneuploidy
      defining this class.
# ---------------- Hereditary axis ----------------
- name: HDGC
  display_name: Hereditary diffuse gastric cancer (germline CDH1/CTNNA1)
  classification: hereditary
  description: >-
    Autosomal dominant syndrome caused by inactivating germline CDH1 variants, and in a
    minority of families CTNNA1, characterised by diffuse gastric cancer and lobular
    breast cancer. Distinct from the somatic diffuse-type subtype above because the
    first hit is constitutional in every gastric epithelial cell, which is what makes
    risk-reducing total gastrectomy a coherent - and recommended - intervention.
  subtype_term:
    preferred_term: hereditary diffuse gastric adenocarcinoma
    term:
      id: MONDO:0007648
      label: hereditary diffuse gastric adenocarcinoma
  genes:
  - preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  - preferred_term: CTNNA1
    term:
      id: hgnc:2509
      label: CTNNA1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    penetrance_percentage: "13-19% cumulative lifetime risk of advanced diffuse gastric cancer"
    expressivity: VARIABLE
    description: >-
      Age-dependent and family-dependent incomplete penetrance. Including less-selected
      families, cumulative lifetime risk of advanced diffuse gastric cancer in CDH1
      carriers is now estimated at 13-19%, well below older high-risk-family estimates
      of roughly 42% in men and 33% in women. CTNNA1 is moderate-penetrance: gastric
      cancer risk is about 7-fold over population baseline versus 38-fold for CDH1.
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer."
    explanation: >-
      IGCLC definition of HDGC, its inheritance mode and its two-tumour phenotype.

inheritance:
- name: Sporadic (multifactorial)
  description: >-
    The overwhelming majority of gastric adenocarcinoma is sporadic and multifactorial,
    driven by H. pylori infection, diet, smoking and age acting on a polygenic
    background. Roughly 10% shows familial clustering, and only about 1-3% is
    attributable to a recognised high-penetrance hereditary syndrome.
  evidence:
  - reference: PMID:36483973
    reference_title: "Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "represents the main risk factor for the onset of gastric neoplasms"
    explanation: >-
      Supports the sporadic/multifactorial framing: an acquired environmental exposure,
      not an inherited variant, is the main driver of gastric neoplasia. The precise
      1-3% hereditary fraction is not quantified by this abstract, hence PARTIAL.
- name: Autosomal dominant (hereditary syndromes)
  description: >-
    The hereditary fraction is dominated by autosomal dominant syndromes: hereditary
    diffuse gastric cancer (CDH1, CTNNA1), Lynch syndrome (MLH1/MSH2/MSH6/PMS2),
    juvenile polyposis (SMAD4), familial adenomatous polyposis and gastric
    adenocarcinoma and proximal polyposis of the stomach (APC), Peutz-Jeghers
    syndrome (STK11) and Li-Fraumeni syndrome (TP53).
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC."
    explanation: >-
      Establishes the two autosomal dominant HDGC genes; HDGC is the archetype of the
      dominant hereditary route to gastric adenocarcinoma.

pathophysiology:
# ================= ROUTE A: intestinal type / Correa cascade =================
- name: Helicobacter pylori Chronic Active Gastritis
  biological_scale: TISSUE
  role: trigger
  conforms_to: "tumor_promoting_inflammation#Chronic Inflammatory Stimulus"
  description: >-
    Persistent colonisation of the gastric mucosa by Helicobacter pylori establishes a
    lifelong, non-resolving active gastritis. The organism cannot be cleared by the
    host response it provokes, so the inflammatory stimulus is indefinite - exactly the
    persistent, non-resolving inflammatory driver pattern the tumor-promoting
    inflammation module abstracts, and which that module names H. pylori gastritis
    preceding gastric cancer as an archetype of. This is the initiating step of the
    Correa cascade and the dominant cause of non-cardia gastric adenocarcinoma.
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  cell_types:
  - preferred_term: gastric epithelial cell
    term:
      id: CL:0002178
      label: epithelial cell of stomach
  locations:
  - preferred_term: gastric mucosa
    term:
      id: UBERON:0001199
      label: mucosa of stomach
  downstream:
  - target: CagA and VacA Virulence Factor Delivery
    description: >-
      Colonising cag-pathogenicity-island-positive strains inject effector proteins
      into the gastric epithelium.
  - target: Pro-Tumorigenic Gastric Inflammatory Microenvironment
    description: >-
      Persistent infection recruits and activates a myeloid-rich mucosal infiltrate.
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial stages of gastritis and atrophy have been linked to excessive salt intake and infection with Helicobacter pylori."
    explanation: >-
      Correa's original formulation places H. pylori infection at the initiating
      gastritis stage of the cascade.
  - reference: PMID:36483973
    reference_title: "Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric environment of 60.3% of the world's population and represents the main risk factor for the onset of gastric neoplasms."
    explanation: >-
      Establishes H. pylori as the principal risk factor for gastric neoplasia and the
      scale of the exposed population.

- name: CagA and VacA Virulence Factor Delivery
  biological_scale: MOLECULAR
  role: mediator
  description: >-
    Strains carrying the cag pathogenicity island use a type IV secretion system to
    translocate the CagA oncoprotein into gastric epithelial cells, where it is tyrosine
    phosphorylated and acts as a promiscuous pathological scaffold, simultaneously
    engaging multiple host signalling pathways and deranging proliferation,
    differentiation and apoptosis. The vacuolating cytotoxin VacA contributes
    independently to epithelial injury. Because transformation, once established, no
    longer requires the oncoprotein, CagA is described as acting by a hit-and-run
    mechanism - a mechanistically important caveat, since it means CagA positivity in
    an established tumour is not required for CagA to have caused it. Note the
    `protein tyrosine kinase activity` annotation on this node refers to the HOST
    kinases (SRC, ABL) that phosphorylate the translocated CagA EPIYA motifs; CagA
    itself is the substrate, not a kinase.
  molecular_functions:
  - preferred_term: host SRC/ABL kinase activity phosphorylating CagA
    modifier: INCREASED
    term:
      id: GO:0004713
      label: protein tyrosine kinase activity
  cell_types:
  - preferred_term: gastric epithelial cell
    term:
      id: CL:0002178
      label: epithelial cell of stomach
  downstream:
  - target: Pro-Tumorigenic Gastric Inflammatory Microenvironment
    description: >-
      CagA-driven epithelial signalling amplifies mucosal cytokine output.
  - target: Atrophic Gastritis and Achlorhydria
    description: >-
      Sustained epithelial injury and inflammation destroy oxyntic glands.
  evidence:
  - reference: PMID:36483973
    reference_title: "Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CagA is the most important virulence factor in H. pylori, and is a translocated oncoprotein that induces morphofunctional modifications in gastric epithelial cells and a chronic inflammatory response that increases the risk of developing precancerous lesions."
    explanation: >-
      Establishes CagA as a translocated oncoprotein linking infection to epithelial
      derangement and precancerous change.
  - reference: PMID:36483973
    reference_title: "Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Upon translocation and tyrosine phosphorylation, CagA moves to the cell membrane and acts as a pathological scaffold protein that simultaneously interacts with multiple intracellular signaling pathways, thereby disrupting cell proliferation, differentiation and apoptosis."
    explanation: >-
      Specifies the molecular mechanism (tyrosine phosphorylation, scaffold function)
      captured by this node's molecular_function annotation.

- name: Pro-Tumorigenic Gastric Inflammatory Microenvironment
  biological_scale: CELLULAR
  role: central_effector
  conforms_to: "tumor_promoting_inflammation#Pro-Tumorigenic Inflammatory Microenvironment"
  description: >-
    The chronically infected mucosa accumulates macrophages, neutrophils and lymphocytes
    that sustain cytokine production (IL-1beta, IL-6, TNF), NF-kB and STAT3 signalling,
    and mutagenic reactive oxygen and nitrogen species. This is the organ-specific
    instance of the module's pro-tumorigenic inflammatory microenvironment: it supplies
    both the proliferative/survival drive and the genotoxic stress that convert
    persistent gastritis into a field at risk of transformation.
  biological_processes:
  - preferred_term: positive regulation of cytokine production
    modifier: INCREASED
    term:
      id: GO:0001819
      label: positive regulation of cytokine production
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  locations:
  - preferred_term: gastric mucosa
    term:
      id: UBERON:0001199
      label: mucosa of stomach
  downstream:
  - target: Atrophic Gastritis and Achlorhydria
    description: >-
      Sustained inflammatory injury destroys oxyntic (acid-secreting) glands.
  evidence:
  - reference: PMID:36483973
    reference_title: "Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "All these alterations in cell biology increase the risk of damaged cells acquiring pro-oncogenic genetic changes."
    explanation: >-
      Links the CagA-driven inflammatory/epithelial derangement to acquisition of
      oncogenic genetic change, the output of this node. Support is PARTIAL: the review
      does not itemise the macrophage/neutrophil infiltrate or the specific
      IL-1beta/IL-6/TNF, NF-kB and STAT3 mediators named in the description, which are
      taken from the conserved module rather than from this source.

- name: Atrophic Gastritis and Achlorhydria
  biological_scale: TISSUE
  role: mediator
  description: >-
    Progressive loss of oxyntic glands (parietal and chief cells) produces multifocal
    atrophic gastritis with reduced or absent gastric acid secretion. Achlorhydria
    removes the stomach's principal antimicrobial barrier, permitting overgrowth of
    nitrate-reducing bacteria and altering the gastric microbiota, which in turn
    increases intragastric nitrosation and N-nitroso compound exposure. This is the
    step at which the mucosa commits to the metaplastic pathway.
  biological_processes:
  - preferred_term: gastric acid secretion
    modifier: DECREASED
    term:
      id: GO:0001696
      label: gastric acid secretion
  locations:
  - preferred_term: gastric mucosa
    term:
      id: UBERON:0001199
      label: mucosa of stomach
  downstream:
  - target: Gastric Intestinal Metaplasia
    description: >-
      The atrophic, achlorhydric mucosa is replaced by intestinal-type epithelium.
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The intermediate stages have been associated with the ingestion of ascorbic acid and nitrate, determinants of intragastric nitrosation."
    explanation: >-
      Correa links the intermediate (atrophy/metaplasia) stages to intragastric
      nitrosation. Support is PARTIAL: the abstract places atrophy in the sequence and
      implicates nitrosation, but does not itself document achlorhydria, loss of the
      antimicrobial barrier, or nitrate-reducing bacterial overgrowth, which are
      asserted in the node description on textbook grounds.

- name: Gastric Intestinal Metaplasia
  biological_scale: TISSUE
  role: mediator
  description: >-
    The gastric mucosal epithelium is replaced by intestinal-type epithelium containing
    goblet and absorptive cells. Intestinal metaplasia is the defining precancerous
    lesion of the intestinal route and the point at which H. pylori eradication begins
    to lose its preventive efficacy - the mechanistic basis for the guideline emphasis
    on eradicating before advanced precancerous change.
  cell_types:
  - preferred_term: gastric goblet cell
    term:
      id: CL:1000313
      label: gastric goblet cell
  locations:
  - preferred_term: gastric mucosa
    term:
      id: UBERON:0001199
      label: mucosa of stomach
  downstream:
  - target: Gastric Dysplasia
    description: >-
      Metaplastic epithelium accumulates further genetic and epigenetic hits and
      becomes cytologically and architecturally atypical.
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence from pathology and epidemiology studies has been provided for a human model of gastric carcinogenesis with the following sequential stages: chronic gastritis; atrophy; intestinal metaplasia; and dysplasia."
    explanation: >-
      The canonical statement of the Correa cascade, placing intestinal metaplasia
      between atrophy and dysplasia.

- name: Gastric Dysplasia
  biological_scale: TISSUE
  role: mediator
  description: >-
    Unequivocally neoplastic but non-invasive epithelium confined by the basement
    membrane, graded low or high. High-grade dysplasia carries substantial short-term
    risk of progression and is the principal target of endoscopic surveillance and
    endoscopic resection. This node is also where the juvenile polyposis route enters
    the graph: germline SMAD4 loss produces gastric polyposis whose hamartomatous polyps
    are the substrate for dysplastic change and subsequent malignancy, a risk not shared
    by BMPR1A carriers.
  genes:
  - preferred_term: SMAD4
    term:
      id: hgnc:6770
      label: SMAD4
  locations:
  - preferred_term: gastric mucosa
    term:
      id: UBERON:0001199
      label: mucosa of stomach
  downstream:
  - target: Intestinal-Type Invasive Adenocarcinoma
    description: >-
      Dysplastic epithelium breaches the basement membrane and invades the lamina
      propria and beyond.
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic gastritis; atrophy; intestinal metaplasia; and dysplasia"
    explanation: >-
      Places dysplasia as the terminal preinvasive stage of the Correa sequence.

- name: Intestinal-Type Invasive Adenocarcinoma
  biological_scale: TISSUE
  role: consequence
  description: >-
    Gland-forming carcinoma invading through the basement membrane into the lamina
    propria, submucosa and, in advanced disease, the muscularis propria and serosa.
    This is the terminal step of the Correa cascade and the histology most strongly
    coupled to the chromosomal-instability molecular class.
  cell_types:
  - preferred_term: glandular epithelial cell of stomach
    term:
      id: CL:0002659
      label: glandular epithelial cell of stomach
  locations:
  - preferred_term: stomach
    term:
      id: UBERON:0000945
      label: stomach
  downstream:
  - target: Chromosomal Instability and Aneuploidy
    description: >-
      Intestinal-type tumours preferentially evolve along the aneuploid CIN trajectory.
  - target: Peritoneal Dissemination and Distant Metastasis
    description: >-
      Invasive carcinoma penetrates the serosa and disseminates.
  - target: Stomach cancer
    description: >-
      Invasive glandular carcinoma of the stomach is the defining neoplastic phenotype.
  - target: Epigastric pain
    description: >-
      Mucosal and mural involvement produces epigastric pain and dyspepsia.
  - target: Gastrointestinal hemorrhage
    description: >-
      Tumour ulceration erodes mucosal vessels, causing occult or overt bleeding.
  - target: Iron deficiency anemia
    description: >-
      Chronic occult blood loss from the ulcerated tumour depletes iron stores.
  - target: Dysphagia
    description: >-
      Proximal (cardia) tumours obstruct the gastric inlet and impair swallowing.
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence from pathology and epidemiology studies has been provided for a human model of gastric carcinogenesis with the following sequential stages: chronic gastritis; atrophy; intestinal metaplasia; and dysplasia."
    explanation: >-
      Anchors the multistep human model leading up to this node. Support is PARTIAL
      because Correa's staged sequence terminates at dysplasia and does not itself
      assert the invasive-carcinoma endpoint.

# ================= ROUTE B: diffuse type / CDH1 =================
- name: CDH1 Inactivation and E-cadherin Loss
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Biallelic inactivation of CDH1 abolishes E-cadherin, the transmembrane
    calcium-dependent adhesion molecule of the epithelial adherens junction. In
    hereditary diffuse gastric cancer the first hit is a germline truncating variant
    present in every gastric epithelial cell and the second hit is most often CDH1
    promoter hypermethylation (or loss of heterozygosity, or somatic mutation); in
    sporadic diffuse cancer both hits are somatic. Germline CTNNA1 truncating variants
    produce the mechanistically equivalent lesion one step down the junction, by
    nonsense-mediated decay of the alpha-E-catenin transcript, but with lower penetrance.
  gene:
    preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  genes:
  - preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  - preferred_term: CTNNA1
    term:
      id: hgnc:2509
      label: CTNNA1
  biological_processes:
  - preferred_term: cell-cell adhesion
    modifier: DECREASED
    term:
      id: GO:0098609
      label: cell-cell adhesion
  cellular_components:
  - preferred_term: adherens junction
    term:
      id: GO:0005912
      label: adherens junction
  downstream:
  - target: Loss of Epithelial Cohesion and Signet Ring Cell Formation
    description: >-
      Without E-cadherin, epithelial cells fail to maintain junctional contacts and
      detach individually from the epithelial sheet.
  - target: Breast carcinoma
    description: >-
      The same adherens-junction lesion acts in breast epithelium, where E-cadherin
      loss produces the lobular breast carcinoma of hereditary diffuse gastric cancer.
  evidence:
  - reference: PMID:9537325
    reference_title: "E-cadherin germline mutations in familial gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the E-cadherin gene revealed a G --> T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product."
    explanation: >-
      The founding observation identifying a truncating germline E-cadherin (CDH1)
      variant as the cause of hereditary diffuse gastric cancer.
  - reference: PMID:40998418
    reference_title: "Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CTNNA1-truncating transcripts are degraded by nonsense-mediated mRNA decay (NMD), and DGCs from germline CTNNA1-truncating carriers lose αE-catenin."
    explanation: >-
      Establishes the loss-of-function mechanism for the CTNNA1 arm - NMD of truncating
      transcripts causing alpha-E-catenin loss at the same adherens junction.

- name: Loss of Epithelial Cohesion and Signet Ring Cell Formation
  biological_scale: CELLULAR
  role: central_effector
  conforms_to: "invasion_and_metastasis#Epithelial-Mesenchymal Transition Activation"
  description: >-
    Loss of E-cadherin releases cells from the epithelial sheet, disrupting apicobasal
    polarity, mitotic spindle orientation and anoikis control. Detached cells accumulate
    intracytoplasmic mucin that displaces the nucleus to the periphery, producing the
    signet-ring morphology. This node conforms to the module's EMT-activation node
    because E-cadherin loss is that node's canonical initiating lesion, but the
    conformance is deliberately scoped to the cadherin-loss / loss-of-adhesion arm only:
    diffuse gastric cancer loses E-cadherin structurally (mutation, promoter
    hypermethylation, LOH) rather than by SNAIL/SLUG/ZEB/TWIST-driven transcriptional
    repression, and does not execute a complete mesenchymal programme. The node
    therefore annotates only decreased cell-cell adhesion, NOT GO:0001837 epithelial to
    mesenchymal transition, which would overstate the biology.
  biological_processes:
  - preferred_term: cell-cell adhesion
    modifier: DECREASED
    term:
      id: GO:0098609
      label: cell-cell adhesion
  cell_types:
  - preferred_term: gastric epithelial cell
    term:
      id: CL:0002178
      label: epithelial cell of stomach
  downstream:
  - target: Diffuse Infiltrative Growth and Linitis Plastica
    description: >-
      Non-cohesive cells permeate the gastric wall singly and in small clusters rather
      than forming a discrete mass.
  evidence:
  - reference: PMID:9537325
    reference_title: "E-cadherin germline mutations in familial gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas."
    explanation: >-
      Ties reduced E-cadherin expression directly to the aggressive, poorly
      differentiated phenotype that this node models as loss of epithelial cohesion.
  - reference: PMID:39379994
    reference_title: "Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable"
    explanation: >-
      Demonstrates that signet-ring-cell foci are the near-universal early cellular
      consequence of germline CDH1 loss, and that their progression is stochastic.

- name: RHOA Gain-of-Function and CLDN18-ARHGAP Fusion
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    A quarter of diffuse gastric carcinomas carry recurrent gain-of-function RHOA
    hotspot mutations (Tyr42, Arg5, Gly17); others carry CLDN18-ARHGAP fusions that
    disable RHO-family GTPase-activating proteins. Both converge on deregulated RHO
    signalling, which sustains survival of non-adherent cells and drives the
    infiltrative, stroma-inducing phenotype. These lesions define the genomically
    stable TCGA class and are essentially absent from intestinal-type tumours.
  gene:
    preferred_term: RHOA
    term:
      id: hgnc:667
      label: RHOA
  genes:
  - preferred_term: RHOA
    term:
      id: hgnc:667
      label: RHOA
  - preferred_term: CLDN18
    term:
      id: hgnc:2039
      label: CLDN18
  molecular_functions:
  - preferred_term: GTPase activity
    modifier: ABNORMAL
    term:
      id: GO:0003924
      label: GTPase activity
  downstream:
  - target: Diffuse Infiltrative Growth and Linitis Plastica
    description: >-
      Deregulated RHO signalling amplifies the infiltrative, stroma-inducing growth
      pattern.
  evidence:
  - reference: PMID:24816255
    reference_title: "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein."
    explanation: >-
      Quantifies RHOA mutation frequency in diffuse gastric carcinoma and identifies the
      specific hotspot residues.
  - reference: PMID:24816255
    reference_title: "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several lines of functional evidence indicated that mutant RHOA works in a gain-of-function manner."
    explanation: >-
      Establishes the gain-of-function (rather than loss-of-function) direction of the
      RHOA lesion asserted by this node.

- name: Diffuse Infiltrative Growth and Linitis Plastica
  biological_scale: TISSUE
  role: consequence
  conforms_to: "invasion_and_metastasis#Local Invasion and Intravasation"
  description: >-
    Non-cohesive tumour cells permeate the gastric wall diffusely, provoking a dense
    desmoplastic stromal reaction. When the process is extensive the stomach becomes a
    rigid, thickened, non-distensible leather-bottle organ - linitis plastica. Because
    there is often no exophytic mass and the overlying mucosa can appear intact,
    endoscopic biopsy is falsely negative more often than in intestinal-type disease,
    contributing to late diagnosis and poor prognosis.
  locations:
  - preferred_term: stomach
    term:
      id: UBERON:0000945
      label: stomach
  downstream:
  - target: Peritoneal Dissemination and Distant Metastasis
    description: >-
      Serosal penetration by non-cohesive cells seeds the peritoneal cavity, the
      characteristic route of spread for diffuse-type disease.
  - target: Stomach cancer
    description: >-
      Diffuse infiltrative carcinoma is the second route to the defining neoplastic
      phenotype.
  - target: Early satiety
    description: >-
      Transmural infiltration with desmoplasia stiffens the gastric wall and reduces
      compliance, limiting the volume tolerated per meal.
  - target: Weight loss
    description: >-
      Reduced gastric capacity and impaired intake drive progressive weight loss.
  evidence:
  - reference: PMID:24816255
    reference_title: "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction."
    explanation: >-
      Directly describes the infiltrative growth with stromal induction that constitutes
      this node.

# ================= SHARED OUTCOME =================
- name: Peritoneal Dissemination and Distant Metastasis
  biological_scale: ORGANISM
  role: outcome
  conforms_to: "invasion_and_metastasis#Metastatic Colonization"
  description: >-
    Both Lauren routes converge on dissemination. Transcoelomic spread after serosal
    penetration seeds the peritoneum and omentum (and, classically, the ovaries as
    Krukenberg tumours); lymphatic spread involves perigastric and distant nodes; and
    haematogenous spread reaches liver, lung and bone. Peritoneal carcinomatosis is the
    dominant and most treatment-refractory pattern in diffuse-type disease and defines
    incurability. Curated in depth in the separate `Metastatic_Gastric_Cancer` entry.
  biological_processes:
  - preferred_term: cell migration
    modifier: INCREASED
    term:
      id: GO:0016477
      label: cell migration
  locations:
  - preferred_term: peritoneum
    term:
      id: UBERON:0002358
      label: peritoneum
  downstream:
  - target: Tumor Immune Evasion and Checkpoint Engagement
    description: >-
      Disseminated tumour deposits persist by engaging inhibitory immune checkpoints.
  - target: Ascites
    description: >-
      Peritoneal carcinomatosis obstructs lymphatic drainage and exudes fluid,
      producing malignant ascites.
  - target: Weight loss
    description: >-
      Disseminated disease drives cancer cachexia with progressive weight loss.
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peritoneal metastases are present in almost 20% of GC at"
    explanation: >-
      Quantifies peritoneal dissemination as present in almost 20% of gastric cancers
      already at diagnosis - direct support for transcoelomic spread as the dominant
      and clinically decisive metastatic route modelled by this node.

# ================= TCGA MOLECULAR CLASS NODES =================
- name: EBV-Driven Hypermethylation and Checkpoint Ligand Amplification
  biological_scale: MOLECULAR
  role: driver
  description: >-
    In roughly 9% of gastric adenocarcinomas, clonal Epstein-Barr virus infection of the
    tumour epithelium drives an extreme CpG island methylator phenotype that silences
    tumour-suppressor loci, together with recurrent PIK3CA mutation and amplification of
    JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). The PD-L1/PD-L2 amplification is the
    mechanistically important part: it makes checkpoint ligand overexpression a
    structural genomic feature rather than an inducible response, which is the rationale
    for prioritising checkpoint blockade in this class. Loss of the SWI/SNF chromatin
    remodeller ARID1A (mutated in 55% of EBV-positive tumours) cooperates with the
    methylator phenotype in this epigenetic reprogramming, while TP53 mutation - dominant
    in the CIN class - is characteristically rare here.
  genes:
  - preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  - preferred_term: CD274
    term:
      id: hgnc:17635
      label: CD274
  - preferred_term: ARID1A
    term:
      id: hgnc:11110
      label: ARID1A
  biological_processes:
  - preferred_term: negative regulation of gene expression, epigenetic
    modifier: INCREASED
    term:
      id: GO:0045814
      label: negative regulation of gene expression, epigenetic
  downstream:
  - target: Tumor Immune Evasion and Checkpoint Engagement
    description: >-
      Amplified PD-L1/PD-L2 directly engages PD-1 on tumour-infiltrating T cells.
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2)"
    explanation: >-
      TCGA defines all three features of this node - PIK3CA mutation, extreme
      hypermethylation, and PD-L1/PD-L2 amplification - in EBV-positive tumours.

- name: Mismatch Repair Deficiency and Microsatellite Instability
  biological_scale: MOLECULAR
  role: driver
  conforms_to: "genome_instability_mutation#Genome-Maintenance Defect or Replication Stress"
  description: >-
    Loss of DNA mismatch repair - usually by sporadic MLH1 promoter hypermethylation,
    less often by a germline Lynch syndrome variant - produces a hypermutated,
    microsatellite-unstable genome. The resulting frameshift neoantigen load makes these
    tumours the most immunotherapy-responsive gastric cancers. This conforms to the
    genome-instability module's mutator-phenotype node, which explicitly covers the
    hypermutated / microsatellite-unstable genome (MMR loss) manifestation.
  genes:
  - preferred_term: MLH1
    term:
      id: hgnc:7127
      label: MLH1
  - preferred_term: MSH2
    term:
      id: hgnc:7325
      label: MSH2
  biological_processes:
  - preferred_term: mismatch repair
    modifier: DECREASED
    term:
      id: GO:0006298
      label: mismatch repair
  downstream:
  - target: Tumor Immune Evasion and Checkpoint Engagement
    description: >-
      Hypermutation generates abundant neoantigens, provoking a T-cell response that the
      tumour must then restrain via checkpoint engagement.
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins"
    explanation: >-
      TCGA characterisation of the MSI class as hypermutated with targetable
      consequences.

- name: Chromosomal Instability and Aneuploidy
  biological_scale: MOLECULAR
  role: driver
  conforms_to: "genome_instability_mutation#Mutator Phenotype and Chromosomal Instability"
  description: >-
    The genome-instability arm of the largest TCGA class. Near-universal TP53 mutation
    disables the checkpoint that would otherwise eliminate cells with missegregated
    chromosomes, permitting tolerated aneuploidy and widespread somatic copy-number
    alteration. Enriched in intestinal histology and at the gastroesophageal junction.
    This node is deliberately kept separate from the receptor-tyrosine-kinase
    amplification it enables, because the two are distinct mechanistic claims and only
    the latter is druggable - a drug that blocks HER2 does not correct chromosomal
    instability.
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  biological_processes:
  - preferred_term: chromosome segregation
    modifier: ABNORMAL
    term:
      id: GO:0007059
      label: chromosome segregation
  downstream:
  - target: Receptor Tyrosine Kinase Amplification
    description: >-
      Copy-number instability generates the focal high-level amplifications of receptor
      tyrosine kinase loci that characterise this class.
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and tumours with chromosomal instability, which show marked aneuploidy"
    explanation: >-
      TCGA definition of the aneuploidy that characterises the CIN class.
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the CIN tumours, we observed TP53 mutations in 71% of tumours."
    explanation: >-
      Quantifies the TP53 loss that permits the tolerated aneuploidy asserted here.

- name: Receptor Tyrosine Kinase Amplification
  biological_scale: MOLECULAR
  role: therapeutic_vulnerability
  description: >-
    Focal high-level amplification of receptor tyrosine kinase loci - ERBB2/HER2 most
    importantly, but also EGFR, MET and FGFR2 - generated by the underlying chromosomal
    instability. Unlike the aneuploidy that produces them, these amplifications are
    directly druggable, and this node is the actual molecular target of trastuzumab and
    of bemarituzumab. It is the mechanistic reason HER2, and now FGFR2b, testing is
    mandatory in advanced disease.
  genes:
  - preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
  - preferred_term: FGFR2
    term:
      id: hgnc:3689
      label: FGFR2
  biological_processes:
  - preferred_term: ERBB2 signaling pathway
    modifier: INCREASED
    term:
      id: GO:0038128
      label: ERBB2 signaling pathway
  downstream:
  - target: Peritoneal Dissemination and Distant Metastasis
    description: >-
      RTK-driven proliferation and survival support progression to disseminated disease.
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "focal amplification of receptor tyrosine kinases"
    explanation: >-
      TCGA identifies focal receptor-tyrosine-kinase amplification as the druggable
      feature of the chromosomally unstable class.
  - reference: PMID:20728210
    reference_title: "Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation"
    explanation: >-
      Confirms HER2 amplification/overexpression as a measurable, therapeutically
      actionable lesion - the property that makes this node a therapeutic vulnerability.

- name: Angiogenic Switch and VEGF-Driven Neovascularization
  biological_scale: TISSUE
  role: therapeutic_vulnerability
  conforms_to: "tumor_angiogenesis#Angiogenic Switch and VEGF-Driven Neovascularization"
  description: >-
    Growing gastric tumours outstrip their blood supply and switch to a pro-angiogenic
    phenotype, secreting VEGF-A that engages VEGFR2 (KDR) on tumour endothelium to drive
    neovascularization. This is the organ-specific instance of the tumour-angiogenesis
    module's central effector, and it is the target of the anti-VEGFR2 antibody
    ramucirumab, which is licensed second-line in advanced gastric adenocarcinoma.
  genes:
  - preferred_term: VEGFA
    term:
      id: hgnc:12680
      label: VEGFA
  - preferred_term: KDR
    term:
      id: hgnc:6307
      label: KDR
  biological_processes:
  - preferred_term: angiogenesis
    modifier: INCREASED
    term:
      id: GO:0001525
      label: angiogenesis
  - preferred_term: vascular endothelial growth factor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0038084
      label: vascular endothelial growth factor signaling pathway
  downstream:
  - target: Peritoneal Dissemination and Distant Metastasis
    description: >-
      Tumour neovascularization sustains growth and provides the haematogenous route for
      dissemination.
  evidence:
  - reference: PMID:32861308
    reference_title: "Gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ramucirumab (anti-angiogenic second line)"
    explanation: >-
      Establishes anti-angiogenic therapy as a licensed treatment class in gastric
      cancer, i.e. that VEGF-driven neovascularization is a validated, druggable node.
  - reference: PMID:25240821
    reference_title: "Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VEGFR-2 has a role in gastric cancer pathogenesis and progression."
    explanation: >-
      States the role of VEGFR2 in gastric cancer pathogenesis, the premise of this
      node and of the ramucirumab indication built on it.

- name: Tumor Immune Evasion and Checkpoint Engagement
  biological_scale: CELLULAR
  role: therapeutic_vulnerability
  description: >-
    Tumour and stromal PD-L1 expression - constitutive in EBV-amplified tumours,
    interferon-induced in the neoantigen-rich MSI class - engages PD-1 on
    tumour-infiltrating CD8-positive T cells and restrains their cytotoxic function.
    Quantified clinically as the PD-L1 combined positive score (CPS), this is the
    directly actionable node: blocking the PD-1/PD-L1 axis with pembrolizumab or
    nivolumab added to chemotherapy improves survival, with benefit concentrated at
    higher CPS and in MSI-high disease.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: negative regulation of T cell mediated immunity
    modifier: INCREASED
    term:
      id: GO:0002710
      label: negative regulation of T cell mediated immunity
  genes:
  - preferred_term: CD274
    term:
      id: hgnc:17635
      label: CD274
  evidence:
  - reference: PMID:37875143
    reference_title: "Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Participants in the pembrolizumab plus chemotherapy group had a significant and clinically meaningful improvement in overall survival with manageable toxicity compared with participants in the placebo plus chemotherapy group."
    explanation: >-
      Therapeutic proof that the PD-1/PD-L1 axis modelled by this node is a functional
      immune brake in gastric adenocarcinoma - blocking it improves survival.
  - reference: PMID:39409957
    reference_title: "Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI)"
    explanation: >-
      Establishes PD-L1 CPS and MSI as mandatory decision biomarkers, i.e. that this
      node is clinically measured and acted upon.

phenotypes:
- category: Clinical
  name: Weight loss
  description: >-
    Unintentional weight loss is one of the commonest presenting features and a marker
    of advanced disease, reflecting reduced intake, gastric outlet compromise and
    cancer cachexia. Downstream of transmural infiltration and of disseminated disease.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
    clinical_course: PROGRESSIVE
  notes: >-
    Clinical presenting features are textbook knowledge. No source in this entry's cited
    corpus states them in snippet-quotable form, so per CLAUDE.md SOP section 4 the claim
    is kept as description/notes rather than attached to a tangential quote.
- category: Clinical
  name: Epigastric pain
  description: >-
    Epigastric pain or dyspepsia, often mild and non-specific initially, is the most
    frequent early symptom and the main reason gastric adenocarcinoma is diagnosed late
    - it is indistinguishable from benign dyspepsia without endoscopy.
  phenotype_term:
    preferred_term: Epigastric pain
    term:
      id: HP:0410019
      label: Epigastric pain
  notes: >-
    Clinical presenting features are textbook knowledge. No source in this entry's cited
    corpus states them in snippet-quotable form, so per CLAUDE.md SOP section 4 the claim
    is kept as description/notes rather than attached to a tangential quote.
- category: Clinical
  name: Early satiety
  description: >-
    Postprandial fullness after small volumes, from reduced gastric compliance in
    diffuse/infiltrative disease or from mechanical outlet compromise in antral tumours.
  phenotype_term:
    preferred_term: Early satiety
    term:
      id: HP:0033842
      label: Early satiety
  notes: >-
    Clinical presenting features are textbook knowledge. No source in this entry's cited
    corpus states them in snippet-quotable form, so per CLAUDE.md SOP section 4 the claim
    is kept as description/notes rather than attached to a tangential quote.
- category: Clinical
  name: Gastrointestinal hemorrhage
  description: >-
    Tumour ulceration causes occult or overt upper gastrointestinal bleeding, presenting
    as melena, haematemesis or asymptomatic iron deficiency.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "particularly in the setting of ulcerated lesions"
    explanation: >-
      Confirms that gastric adenocarcinoma commonly presents as an ulcerated lesion,
      the substrate for gastrointestinal haemorrhage.
- category: Laboratory
  name: Iron deficiency anemia
  description: >-
    Chronic occult blood loss from an ulcerated tumour produces microcytic iron
    deficiency anaemia, frequently the first objective abnormality and a recognised
    indication for upper endoscopy.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  notes: >-
    Clinical presenting features are textbook knowledge. No source in this entry's cited
    corpus states them in snippet-quotable form, so per CLAUDE.md SOP section 4 the claim
    is kept as description/notes rather than attached to a tangential quote.
- category: Clinical
  name: Dysphagia
  description: >-
    Difficulty swallowing, characteristic of proximal (cardia) and gastroesophageal
    junction tumours obstructing the gastric inlet.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
    clinical_course: PROGRESSIVE
  notes: >-
    Clinical presenting features are textbook knowledge. No source in this entry's cited
    corpus states them in snippet-quotable form, so per CLAUDE.md SOP section 4 the claim
    is kept as description/notes rather than attached to a tangential quote.
- category: Clinical
  name: Ascites
  description: >-
    Malignant ascites from peritoneal carcinomatosis, the dominant pattern of spread in
    diffuse-type disease and a marker of incurability.
  phenotype_term:
    preferred_term: Malignant ascites
    term:
      id: HP:0001541
      label: Ascites
  notes: >-
    Clinical presenting features are textbook knowledge. No source in this entry's cited
    corpus states them in snippet-quotable form, so per CLAUDE.md SOP section 4 the claim
    is kept as description/notes rather than attached to a tangential quote.
- category: Neoplasm
  name: Stomach cancer
  description: >-
    The defining neoplastic phenotype - a malignant epithelial tumour of the stomach,
    the endpoint of both the intestinal and diffuse mechanistic routes modelled here.
  phenotype_term:
    preferred_term: Stomach cancer
    term:
      id: HP:0012126
      label: Stomach cancer
  evidence:
  - reference: PMID:38572751
    reference_title: "Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%)"
    explanation: >-
      Establishes stomach cancer as a distinct, quantified disease entity in global
      cancer surveillance.
- category: Neoplasm
  name: Breast carcinoma
  description: >-
    Lobular breast carcinoma is the second tumour of hereditary diffuse gastric cancer.
    Female germline CDH1 carriers have substantially increased lobular breast cancer
    risk and require dedicated breast surveillance in addition to gastric risk
    management; the same tumour type recurs in CTNNA1-truncating carriers. Mechanistically
    downstream of the same CDH1/CTNNA1 adherens-junction lesion, expressed in breast
    rather than gastric epithelium.
  subtype: HDGC
  phenotype_term:
    preferred_term: Lobular breast carcinoma
    term:
      id: HP:0003002
      label: Breast carcinoma
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer."
    explanation: >-
      IGCLC guidelines establish lobular breast cancer as a defining component of the
      HDGC phenotype.
  - reference: PMID:40998418
    reference_title: "Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LBC is recurrent among CTNNA1-truncating carriers, some lacking HDGC criteria."
    explanation: >-
      Extends the lobular breast cancer phenotype to the CTNNA1 arm, including carriers
      who do not meet classical HDGC criteria.

histopathology:
- name: Intestinal Metaplasia of Gastric Mucosa
  description: >-
    Replacement of gastric mucosal epithelium by intestinal-type epithelium with goblet
    cells. The defining precancerous lesion of the intestinal (Correa) route and the
    histologic finding that triggers endoscopic surveillance.
  finding_term:
    preferred_term: Intestinal Metaplasia of Gastric Mucosa
    term:
      id: NCIT:C3956
      label: Intestinal Metaplasia of Gastric Mucosa
  diagnostic: false
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic gastritis; atrophy; intestinal metaplasia; and dysplasia"
    explanation: >-
      Establishes intestinal metaplasia as a defined histologic stage of the human
      gastric carcinogenesis sequence.
- name: Gastric Dysplasia
  description: >-
    Unequivocally neoplastic non-invasive epithelium, graded low or high. High-grade
    dysplasia is the immediate precursor of invasive carcinoma and an indication for
    endoscopic resection.
  finding_term:
    preferred_term: Gastric Dysplasia
    term:
      id: NCIT:C95754
      label: Gastric Dysplasia
  diagnostic: false
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with the following sequential stages: chronic gastritis; atrophy; intestinal metaplasia; and dysplasia"
    explanation: >-
      Places dysplasia as the final preinvasive histologic stage of the Correa sequence.
- name: Poorly Cohesive Growth Pattern
  description: >-
    Malignant cells infiltrating singly or in tiny aggregates rather than forming
    glands - the architectural hallmark of diffuse-type (poorly cohesive) carcinoma in
    the current WHO scheme and the direct histologic readout of E-cadherin loss.
  finding_term:
    preferred_term: Poorly Cohesive Malignant Cellular Infiltrate
    term:
      id: NCIT:C95744
      label: Poorly Cohesive Malignant Cellular Infiltrate
  diagnostic: false
  evidence:
  - reference: PMID:24816255
    reference_title: "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa"
    explanation: >-
      Describes the poorly differentiated, non-gland-forming histology of the diffuse
      tumours in which RHOA mutations occur.
- name: Signet Ring Cell Morphology
  description: >-
    The characteristic cytology of the diffuse type: tumour cells distended by
    intracytoplasmic mucin that displaces the nucleus to the cell periphery, producing a
    signet-ring outline. Signet-ring foci are near-universal as pT1a lesions in
    prophylactic gastrectomy specimens from germline CDH1 carriers, where the behaviour
    of any individual focus is unpredictable.
  finding_term:
    preferred_term: Gastric Signet Ring Cell Adenocarcinoma
    term:
      id: NCIT:C5250
      label: Gastric Signet Ring Cell Adenocarcinoma
  frequency: VERY_FREQUENT
  subtype: HDGC
  diagnostic: false
  evidence:
  - reference: PMID:39379994
    reference_title: "Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "almost every PTG specimen shows the presence of small low-stage (pT1a) signet ring cell (SRC) lesions of which the behaviour is unpredictable but often are considered indolent or premalignant stages of DGC"
    explanation: >-
      "Almost every" prophylactic total gastrectomy specimen maps to the VERY_FREQUENT
      band; the frequency is scoped to the HDGC subtype, where the quantitative claim
      was made, not to gastric adenocarcinoma overall.

biochemical:
- name: HER2 (ERBB2) Overexpression or Amplification
  notes: >-
    Assessed by immunohistochemistry with reflex in-situ hybridisation for equivocal
    (2+) cases. Positive in roughly 15-20% of gastric and gastroesophageal junction
    adenocarcinomas, enriched in intestinal-type and junctional tumours. Expression is
    notoriously heterogeneous within a tumour, so adequate tissue sampling matters.
    A mandatory first-line decision biomarker.
  biomarker_term:
    preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
  evidence:
  - reference: PMID:39409957
    reference_title: "Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI)"
    explanation: >-
      Establishes HER2 as one of the four essential biomarkers determining therapy
      selection in advanced gastric adenocarcinoma.
- name: PD-L1 Combined Positive Score (CPS)
  notes: >-
    Immunohistochemical score counting PD-L1-staining tumour cells, lymphocytes and
    macrophages relative to total viable tumour cells. Assay- and
    jurisdiction-specific thresholds (commonly CPS >= 1, >= 5 or >= 10) gate access to
    first-line checkpoint blockade; benefit in KEYNOTE-859 was greater at higher CPS.
  biomarker_term:
    preferred_term: CD274
    term:
      id: hgnc:17635
      label: CD274
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in tumor cells, lymphocytes, and macrophages relative to the total number of viable tumor cells, and is expressed as a score."
    explanation: >-
      Defines exactly what the PD-L1 combined positive score counts, as curated here.
- name: Mismatch Repair / Microsatellite Instability Status
  notes: >-
    Determined by immunohistochemistry for MLH1, PMS2, MSH2 and MSH6, and/or by PCR or
    NGS microsatellite testing. dMMR/MSI-H tumours are strongly immunotherapy-sensitive
    and, when germline, indicate Lynch syndrome and trigger cascade testing.
  biomarker_term:
    preferred_term: MLH1
    term:
      id: hgnc:7127
      label: MLH1
  evidence:
  - reference: PMID:38160327
    reference_title: "The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients"
    explanation: >-
      Guideline confirmation that dMMR/MSI-H status directs distinct management in
      gastric cancer.
- name: Claudin-18.2 (CLDN18.2) Expression
  notes: >-
    Tight-junction protein whose stomach-specific isoform 2 is retained and becomes
    surface-exposed in a large fraction of gastric adenocarcinomas while normal-tissue
    expression is confined to short-lived differentiated gastric mucosal epithelium -
    an unusually clean therapeutic window. Trial-validated positivity is >= 75% of
    tumour cells with moderate-to-strong membranous staining; this threshold gates
    zolbetuximab eligibility.
  biomarker_term:
    preferred_term: CLDN18
    term:
      id: hgnc:2039
      label: CLDN18
  evidence:
  - reference: PMID:37068504
    reference_title: "Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CLDN18.2-positive (defined as ≥75% of tumour cells showing moderate-to-strong membranous CLDN18 staining)"
    explanation: >-
      Gives the exact trial-validated CLDN18.2 positivity threshold curated here.

genetic:
- name: CDH1
  notes: >-
    Tumour suppressor encoding E-cadherin. Germline inactivating variants cause
    hereditary diffuse gastric cancer; somatic biallelic inactivation (frequently via
    promoter hypermethylation) underlies sporadic diffuse-type disease. Truncating
    variants are readily classifiable; missense variants often remain VUS without
    functional or segregation data.
  gene_term:
    preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: HDGC
  evidence:
  - reference: PMID:9537325
    reference_title: "E-cadherin germline mutations in familial gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer in a large kindred from New Zealand (Aotearoa)."
    explanation: >-
      The original identification of CDH1 as the hereditary diffuse gastric cancer gene.
  - reference: PMID:40998418
    reference_title: "Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with wild-type individuals, GC risk is 7-fold higher in CTNNA1-truncating and 38-fold higher in CDH1-truncating variant carriers."
    explanation: >-
      Quantifies the 38-fold gastric cancer risk of CDH1 truncating variants against
      population controls, and calibrates it against CTNNA1.
- name: CTNNA1
  notes: >-
    Encodes alpha-E-catenin, which links E-cadherin to the actin cytoskeleton. Germline
    truncating variants cause a moderate-penetrance HDGC phenotype through
    nonsense-mediated decay of the transcript. Accounts for under 2% of HDGC families;
    gastric cancer risk is roughly fivefold lower than for CDH1, which is why
    management (surveillance versus prophylactic gastrectomy) is not simply
    transplanted from CDH1.
  gene_term:
    preferred_term: CTNNA1
    term:
      id: hgnc:2509
      label: CTNNA1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: HDGC
  evidence:
  - reference: PMID:40998418
    reference_title: "Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrate that compared with CDH1, CTNNA1 is a moderate penetrance HDGC gene."
    explanation: >-
      The key calibration statement establishing CTNNA1 as moderate- rather than
      high-penetrance, which is what makes its management distinct from CDH1.
  - reference: PMID:40998418
    reference_title: "Hereditary diffuse gastric cancer spectrum associated with germline CTNNA1 loss of function revealed by clinical and molecular data from 351 carrier families and over 37 000 non-carrier controls."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DGC risk is eightfold higher in truncating, compared with non-truncating carriers."
    explanation: >-
      Establishes that only truncating CTNNA1 variants carry substantial diffuse gastric
      cancer risk - a variant-type distinction that matters for clinical reporting.
- name: RHOA
  notes: >-
    Small GTPase recurrently mutated at Tyr42, Arg5 and Gly17 in about a quarter of
    diffuse-type gastric carcinomas, acting in a gain-of-function manner. Defines part
    of the genomically stable TCGA class and is specific to diffuse histology. Not yet
    directly druggable.
  gene_term:
    preferred_term: RHOA
    term:
      id: hgnc:667
      label: RHOA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: Diffuse
  evidence:
  - reference: PMID:24816255
    reference_title: "Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comparison of mutational profiles for the major gastric cancer subtypes showed that RHOA mutations occur specifically in DGCs"
    explanation: >-
      Establishes the histology specificity of RHOA mutation to diffuse gastric
      carcinoma, supporting its placement on the diffuse route only.
- name: ERBB2
  notes: >-
    Receptor tyrosine kinase amplified or overexpressed in roughly 15-20% of gastric and
    gastroesophageal junction adenocarcinomas, concentrated in the chromosomal
    instability class. The first successfully drugged target in this disease.
  gene_term:
    preferred_term: ERBB2
    term:
      id: hgnc:3430
      label: ERBB2
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: CIN
  evidence:
  - reference: PMID:20728210
    reference_title: "Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumours showed overexpression of HER2 protein by immunohistochemistry or gene amplification by fluorescence in-situ hybridisation."
    explanation: >-
      Defines the HER2 overexpression/amplification lesion as a tumour-intrinsic,
      therapeutically actionable alteration in gastric adenocarcinoma.
- name: FGFR2
  notes: >-
    Receptor tyrosine kinase whose FGFR2b isoform is overexpressed in a minority of
    gastric adenocarcinomas, most often through FGFR2 amplification within the
    chromosomal instability class. Target of bemarituzumab.
  gene_term:
    preferred_term: FGFR2
    term:
      id: hgnc:3689
      label: FGFR2
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: CIN
  evidence:
  - reference: PMID:36244398
    reference_title: "Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "910 patients were screened and 155 were randomly assigned to the bemarituzumab"
    explanation: >-
      The 910-screened-to-155-enrolled ratio quantifies how small the
      FGFR2b-overexpressing subset of gastric adenocarcinoma is.
- name: MLH1
  notes: >-
    Mismatch repair gene. Sporadic MSI-high gastric cancer arises chiefly through MLH1
    promoter hypermethylation; germline pathogenic variants cause Lynch syndrome. MLH1
    loss on immunohistochemistry is the usual entry point to MSI testing.
  gene_term:
    preferred_term: MLH1
    term:
      id: hgnc:7127
      label: MLH1
  relationship_type: CAUSATIVE
  subtype: MSI
  evidence:
  - reference: PMID:31337882
    reference_title: "Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes"
    explanation: >-
      Establishes MLH1 (with MSH2) as a high-penetrance dominant cancer-predisposition
      gene, the Lynch route into gastric adenocarcinoma.
- name: MSH2
  notes: >-
    Mismatch repair gene. Within Lynch syndrome, MSH2 carriers specifically carry
    elevated upper gastrointestinal cancer risk with age - the gene most relevant to the
    Lynch contribution to gastric adenocarcinoma. See the `Lynch_Syndrome` entry for the
    full syndromic context.
  gene_term:
    preferred_term: MSH2
    term:
      id: hgnc:7325
      label: MSH2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: MSI
  evidence:
  - reference: PMID:31337882
    reference_title: "Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate"
    explanation: >-
      Prospective evidence that upper gastrointestinal (including gastric) cancer risk in
      Lynch syndrome is concentrated in older MSH2 carriers.
- name: SMAD4
  notes: >-
    Juvenile polyposis syndrome gene. Gastric polyposis and gastric malignancy in
    juvenile polyposis are specifically associated with SMAD4, not with BMPR1A - a
    genotype-phenotype distinction with direct surveillance consequences, since it means
    gastric surveillance is warranted in SMAD4 carriers but is not supported by the
    published BMPR1A phenotype.
  gene_term:
    preferred_term: SMAD4
    term:
      id: hgnc:6770
      label: SMAD4
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:37400896
    reference_title: "Genotype-phenotype correlation of BMPR1a disease causing variants in juvenile polyposis syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike in SMAD4 carriers, gastric polyposis and malignancy were not identified in our review in BMPR1a carriers"
    explanation: >-
      Establishes that within juvenile polyposis the gastric cancer risk is
      SMAD4-specific, preventing the common overstatement that juvenile polyposis as a
      whole confers gastric risk. Support is PARTIAL because this is a BMPR1A-focused
      study and the SMAD4 association is carried by the negative finding in its
      comparator arm rather than measured directly.
- name: ARID1A
  notes: >-
    Chromatin-remodelling (SWI/SNF) tumour suppressor, among the most frequently mutated
    genes in gastric adenocarcinoma overall and strongly enriched in the EBV-positive and
    MSI classes. Loss remodels chromatin and cooperates with the epigenetic
    reprogramming modelled on the EBV node.
  gene_term:
    preferred_term: ARID1A
    term:
      id: hgnc:11110
      label: ARID1A
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: EBV-positive
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EBV-positive tumours had frequent ARID1A (55%) and BCOR (23%) mutations and only rare TP53 mutations."
    explanation: >-
      Quantifies ARID1A mutation in 55% of EBV-positive gastric adenocarcinomas and
      contrasts the near-absence of TP53 mutation in that class with its dominance in CIN.
- name: PIK3CA
  notes: >-
    Recurrently mutated in EBV-positive gastric adenocarcinoma, where it is one of the
    three defining molecular features alongside extreme hypermethylation and PD-L1/L2
    amplification.
  gene_term:
    preferred_term: PIK3CA
    term:
      id: hgnc:8975
      label: PIK3CA
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: EBV-positive
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations"
    explanation: >-
      TCGA identifies recurrent PIK3CA mutation as a defining feature of EBV-positive
      gastric adenocarcinoma.
- name: TP53
  notes: >-
    The most frequently mutated gene in gastric adenocarcinoma overall and near-universal
    in the chromosomal instability class, where loss of p53 checkpoint control permits
    the tolerated aneuploidy that defines the class.
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  subtype: CIN
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the CIN tumours, we observed TP53 mutations in 71% of tumours."
    explanation: >-
      Directly quantifies TP53 mutation in 71% of chromosomally unstable gastric
      adenocarcinomas, the permissive lesion for the tolerated aneuploidy that defines
      the class.

environmental:
- name: Helicobacter pylori infection
  description: >-
    The dominant modifiable cause and the main risk factor for gastric neoplasia, present
    in roughly 60% of the world's population. Widely cited attributable-fraction
    estimates put close to 90% of non-cardia gastric adenocarcinoma down to H. pylori,
    and IARC classifies it a Group 1 carcinogen; neither the 90% figure nor the IARC
    classification is snippet-quotable from the sources cited in this entry, so both are
    reported as context rather than as evidenced claims. Eradication reduces incidence,
    most effectively before advanced atrophy and metaplasia develop.
  evidence:
  - reference: PMID:36483973
    reference_title: "Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "represents the main risk factor for the onset of gastric neoplasms"
    explanation: >-
      Establishes H. pylori as the principal risk factor for gastric neoplasia.
- name: High dietary salt and salt-preserved foods
  description: >-
    High sodium intake and consumption of salt-preserved and nitrosated foods damage the
    gastric mucosa, potentiate H. pylori colonisation, and supply nitrosating precursors
    - contributing at both the initiating and the later stages of the Correa cascade.
  evidence:
  - reference: PMID:1458460
    reference_title: "Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The final stages have been linked with the supply of beta-carotene and with excessive salt intake."
    explanation: >-
      Correa implicates excessive salt intake at the final stages of gastric
      carcinogenesis; the same abstract separately links the initial gastritis/atrophy
      stages to salt, quoted on the H. pylori gastritis node.
- name: Tobacco smoking
  description: >-
    An established risk factor for gastric adenocarcinoma at both cardia and non-cardia
    sites, acting independently of and additively with H. pylori infection.
  evidence:
  - reference: PMID:38572751
    reference_title: "Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "targeting of key risk factors for cancer (including smoking, overweight and obesity, and infection)"
    explanation: >-
      Indirect: GLOBOCAN names smoking and infection among the key modifiable cancer risk
      factors amenable to prevention. Gastric-specific risk magnitude is not quantified
      here.

diagnosis:
- name: Upper endoscopy with multiple biopsies
  description: >-
    The diagnostic gold standard. Multiple biopsies are essential because single samples
    substantially underperform, particularly with ulcerated lesions and in diffuse-type
    disease where the mucosa may look intact over transmural infiltration.
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multiple biopsies should be carried out to provide sufficient material for histological and molecular interpretation, particularly in the setting of ulcerated lesions."
    explanation: >-
      Guideline statement on the multiple-biopsy requirement and its rationale.
- name: CT staging and diagnostic laparoscopy with peritoneal lavage
  description: >-
    Thoracic and abdomino-pelvic CT is the primary staging examination; endoscopic
    ultrasound refines T and N assessment. Diagnostic laparoscopy with peritoneal
    washings is added for potentially resectable locally advanced disease to detect
    occult peritoneal spread, since positive cytology counts as metastatic disease.
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thoracic and abdomino-pelvic CT scan is the preferred examination for staging and is highly accurate in detect- ing metastasis; albeit less sensitive for evaluating T and N spread."
    explanation: >-
      Establishes CT as the preferred staging modality and its known limitation for local
      T/N assessment, which is why EUS and laparoscopy are added.
- name: Predictive biomarker panel
  description: >-
    Advanced disease requires HER2 (IHC with reflex ISH), MMR/MSI, PD-L1 CPS and
    claudin-18.2 testing before first-line therapy. EBER in-situ hybridisation, broad
    NGS and ctDNA are selective or investigational.
  evidence:
  - reference: PMID:39409957
    reference_title: "Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI)"
    explanation: >-
      Names the exact four-biomarker panel curated here as essential for therapy
      selection.

differential_diagnoses:
- name: Gastric MALT lymphoma
  description: >-
    The most important differential to keep mechanistically separate. Extranodal marginal
    zone B-cell lymphoma of mucosa-associated lymphoid tissue shares H. pylori as its
    driver, arises in the same organ, and can look similar endoscopically - but it is a
    lymphoid, not epithelial, neoplasm with an entirely different natural history and
    first-line treatment. Curated separately as `MALT_Lymphoma`.
  disease_term:
    preferred_term: MALT lymphoma
    term:
      id: MONDO:0007650
      label: MALT lymphoma
  distinguishing_features:
  - Cell of origin is a marginal-zone B lymphocyte, not gastric glandular epithelium;
    immunohistochemistry (CD20-positive lymphoid infiltrate with lymphoepithelial
    lesions) separates them definitively.
  - Characteristic t(11;18)(q21;q21) API2-MALT1 translocation has no counterpart in
    gastric adenocarcinoma, and predicts failure of eradication therapy.
  - H. pylori eradication alone can induce durable remission in early-stage gastric MALT
    lymphoma; eradication never treats established gastric adenocarcinoma, in which it
    is a primary-prevention measure only.
  - Indolent course with prolonged survival, versus the aggressive course of
    adenocarcinoma.
  notes: >-
    The distinguishing features rest on standard WHO diagnostic pathology rather than on
    any source in this entry's cited corpus, so no evidence item is attached rather than
    citing a tangential quote (CLAUDE.md SOP section 4).
- name: Gastrointestinal stromal tumor
  description: >-
    Mesenchymal neoplasm of the interstitial cells of Cajal, the commonest gastric
    submucosal tumour. Presents as a submucosal mass with intact overlying mucosa, so
    superficial endoscopic biopsy is frequently non-diagnostic - the same pitfall as
    diffuse-type adenocarcinoma, but with a completely different answer. Curated
    separately as `Gastrointestinal_Stromal_Tumor`.
  disease_term:
    preferred_term: gastrointestinal stromal tumor
    term:
      id: MONDO:0011719
      label: gastrointestinal stromal tumor
  distinguishing_features:
  - KIT (CD117) and DOG1 positive, cytokeratin negative - the inverse of adenocarcinoma.
  - Driven by activating KIT or PDGFRA mutations and treated with imatinib; neither
    applies to adenocarcinoma.
  - Spindle or epithelioid mesenchymal morphology without gland formation or signet-ring
    cells.
  notes: >-
    The distinguishing features rest on standard WHO diagnostic pathology rather than on
    any source in this entry's cited corpus, so no evidence item is attached rather than
    citing a tangential quote (CLAUDE.md SOP section 4).
- name: Gastric neuroendocrine neoplasm
  description: >-
    Epithelial neoplasm of enterochromaffin-like cells. Type 1 lesions arise in
    autoimmune atrophic gastritis with hypergastrinaemia - the same atrophic background
    that predisposes to intestinal-type adenocarcinoma - so the two can coexist and must
    be distinguished on a single biopsy. Curated separately as
    `Gastroenteropancreatic_Neuroendocrine_Neoplasm`.
  disease_term:
    preferred_term: gastric neuroendocrine neoplasm
    term:
      id: MONDO:0003111
      label: gastric neuroendocrine neoplasm
  distinguishing_features:
  - Expresses chromogranin A and synaptophysin with organoid/trabecular architecture,
    unlike gland-forming adenocarcinoma.
  - Type 1 lesions are gastrin-driven, usually multiple, small and indolent, and are
    managed by surveillance or endoscopic resection rather than gastrectomy.
  - Graded by Ki-67 index and mitotic count (WHO neuroendocrine grading), not by Lauren
    type.
  notes: >-
    The distinguishing features rest on standard WHO diagnostic pathology rather than on
    any source in this entry's cited corpus, so no evidence item is attached rather than
    citing a tangential quote (CLAUDE.md SOP section 4).
- name: Gastroesophageal junction adenocarcinoma
  description: >-
    Adenocarcinoma centred at the gastroesophageal junction. Deliberately modelled as a
    differential rather than a subtype: junctional tumours share systemic-therapy
    evidence with gastric adenocarcinoma (they were co-enrolled in ToGA, FLOT4,
    SPOTLIGHT and FIGHT) but differ in aetiology, being driven by obesity and reflux
    rather than H. pylori, and overlapping the Barrett-derived esophageal
    adenocarcinoma biology curated in `Esophageal_Adenocarcinoma`.
  disease_term:
    preferred_term: gastroesophageal junction adenocarcinoma
    term:
      id: MONDO:0003219
      label: gastroesophageal junction adenocarcinoma
  distinguishing_features:
  - Anatomic epicentre at the junction (Siewert classification) rather than in the
    gastric body or antrum.
  - Aetiologically linked to gastroesophageal reflux, Barrett metaplasia and obesity,
    not to H. pylori-driven atrophic gastritis.
  - Higher HER2 positivity rate than distal gastric tumours, and different locoregional
    management (chemoradiation has a defined role at the junction).
  evidence:
  - reference: PMID:39409957
    reference_title: "Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction"
    explanation: >-
      Confirms that junctional adenocarcinoma is handled alongside, but named separately
      from, gastric adenocarcinoma in systemic-therapy guidance - exactly the boundary
      modelled here.
- name: Benign gastric ulcer
  description: >-
    Peptic ulceration, most often H. pylori- or NSAID-related. Endoscopically an
    ulcerated gastric adenocarcinoma can be indistinguishable from a benign ulcer, which
    is why guidelines mandate biopsy of every gastric ulcer and endoscopic confirmation
    of healing. Curated separately as `Gastric_Ulcer`.
  disease_term:
    preferred_term: gastric ulcer
    term:
      id: MONDO:0001126
      label: gastric ulcer
  distinguishing_features:
  - Histology shows inflammation, granulation tissue and regenerative change without
    invasive malignant epithelium.
  - Benign ulcers heal completely on acid suppression and H. pylori eradication;
    persistent or non-healing ulceration mandates re-biopsy for malignancy.
  - Regular ulcer margins with radiating folds, versus the heaped, irregular, indurated
    margins of a malignant ulcer.
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "particularly in the setting of ulcerated lesions"
    explanation: >-
      The guideline singles out ulcerated lesions as requiring extra biopsy sampling,
      reflecting the difficulty of separating malignant from benign gastric ulceration.

treatments:
- name: Prophylactic Total Gastrectomy for Germline CDH1 Carriers
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    The highest-stakes actionable recommendation in this entry. For carriers of a
    pathogenic germline CDH1 variant, risk-reducing total gastrectomy remains the IGCLC
    recommended option for gastric cancer risk management, and is the only intervention
    that substantially eliminates it (rare post-gastrectomy diffuse gastric cancer is
    reported from residual mucosa at the anastomosis). Threshold and timing: surgery is
    recommended in early adulthood, generally between 20 and 30 years of age, and is NOT
    recommended over age 70 unless there are significant mitigating circumstances. For
    carriers who decline or postpone, the IGCLC recommends annual endoscopy by
    endoscopists experienced in HDGC, and eradication of Helicobacter pylori if present.
    The 2020 IGCLC guidelines
    relaxed the genetic testing criteria (mainly by loosening age limits) and, critically,
    now express increasing confidence that endoscopic surveillance in expert centres can
    be safely offered to carriers who wish to postpone surgery or whose risk is not well
    defined - so the recommendation is no longer uniform. The reason the threshold has
    moved is quantitative: including less-selected families, the cumulative lifetime risk
    of advanced diffuse gastric cancer is now estimated at 13-19%, far below older
    high-risk-family estimates, while roughly a third of carriers decline surgery because
    of its lifelong physical and psychological consequences. Surveillance is imperfect:
    almost every prophylactic gastrectomy specimen already contains small pT1a
    signet-ring-cell foci of unpredictable behaviour, so the goal of endoscopic
    surveillance must be detecting atypical deeper-infiltrating lesions rather than every
    signet-ring focus. CTNNA1 carriers should not be managed by simple extrapolation from
    CDH1, being moderate-penetrance. Lifelong sequelae of total gastrectomy include small
    frequent meals, weight loss, dumping, reflux, and iron and vitamin B12 deficiency.
  treatment_term:
    preferred_term: Total Gastrectomy
    term:
      id: NCIT:C185240
      label: Total Gastrectomy
  target_mechanisms:
  - target: CDH1 Inactivation and E-cadherin Loss
    treatment_effect: INHIBITS
    description: >-
      Removes the entire at-risk epithelial compartment in which the germline first hit
      is present, pre-empting the somatic second hit.
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers."
    explanation: >-
      The core IGCLC recommendation curated here.
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Where possible, surgery is recommended in early adulthood, generally between 20 and 30yrs of age."
    explanation: >-
      The IGCLC age window for risk-reducing total gastrectomy - the timing threshold
      this treatment entry turns on.
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PTG is not recommended in patients over 70yrs unless there are significant mitigating circumstances."
    explanation: >-
      The upper age bound, driven by perioperative risk and prolonged recovery.
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For those declining or wishing to postpone PTG, it is recommended that annual endoscopy is carried out by experienced endoscopists with knowledge of HDGC"
    explanation: >-
      Defines the surveillance alternative and its required expertise, and links this
      treatment to the Endoscopic Surveillance entry.
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is also recommended that Helicobacter pylori is eradicated if present."
    explanation: >-
      Co-recommendation for CDH1 carriers, linking the hereditary arm to the H. pylori
      screen-and-treat entry.
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined."
    explanation: >-
      Documents the qualification to the blanket recommendation - the surveillance
      alternative and the conditions under which it is acceptable.
  - reference: PMID:39379994
    reference_title: "Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the cumulative lifetime risk of developing advanced DGC is much lower than previously thought and is now estimated to be 13-19%"
    explanation: >-
      Gives the revised quantitative risk estimate that is driving reconsideration of a
      uniform prophylactic gastrectomy recommendation.
  - reference: PMID:39379994
    reference_title: "Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a prophylactic total gastrectomy (PTG) is currently the gold standard for reducing the risk of DGC in CDH1 PV carriers"
    explanation: >-
      Independent confirmation of prophylactic total gastrectomy as the gold-standard
      risk-reducing intervention.
- name: Curative Gastrectomy with D2 Lymphadenectomy
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    The definitive operation for non-early, operable gastric adenocarcinoma: subtotal or
    total gastrectomy with a D2 lymphadenectomy clearing the perigastric mesenteric and
    coeliac-branch nodal stations. Distinct from the prophylactic total gastrectomy
    offered to unaffected germline CDH1 carriers - this is resection of established
    cancer with curative intent, and is normally combined with perioperative
    chemotherapy.
  treatment_term:
    preferred_term: Gastrectomy
    term:
      id: NCIT:C15236
      label: Gastrectomy
  target_mechanisms:
  - target: Intestinal-Type Invasive Adenocarcinoma
    treatment_effect: INHIBITS
    description: >-
      Removes the invasive primary tumour and its draining nodal basin before
      dissemination becomes established.
  - target: Diffuse Infiltrative Growth and Linitis Plastica
    treatment_effect: INHIBITS
    description: >-
      Resects transmurally infiltrating disease; total gastrectomy is usually required
      because diffuse tumours lack a discrete margin.
  evidence:
  - reference: PMID:32861308
    reference_title: "Gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches)."
    explanation: >-
      Defines the standard curative operation and the required extent of lymphadenectomy.
  - reference: PMID:32861308
    reference_title: "Gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers."
    explanation: >-
      Establishes that surgery is combined with perioperative/adjuvant chemotherapy from
      stage 1B upward, linking this entry to the FLOT treatment.

- name: Ramucirumab (Anti-VEGFR2) Second-Line Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Human IgG1 monoclonal antibody antagonist of VEGFR2 (KDR), licensed second line in
    advanced gastric and gastroesophageal junction adenocarcinoma, given with paclitaxel
    (RAINBOW) or as monotherapy (REGARD). It is the only anti-angiogenic agent with
    phase 3 survival benefit in this disease and, unlike the HER2, CLDN18.2, PD-L1 and
    FGFR2b agents, requires no predictive biomarker. Characteristic class toxicities are
    hypertension, proteinuria and bleeding.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ramucirumab
      term:
        id: NCIT:C70792
        label: Ramucirumab
  target_mechanisms:
  - target: Angiogenic Switch and VEGF-Driven Neovascularization
    treatment_effect: INHIBITS
    description: >-
      Blocks VEGFR2 on tumour endothelium, cutting off the VEGF-driven neovascularization
      that sustains tumour growth.
  evidence:
  - reference: PMID:25240821
    reference_title: "Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel."
    explanation: >-
      Defines the agent, its molecular target and the second-line indication curated here.
  - reference: PMID:32861308
    reference_title: "Gastric cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line)."
    explanation: >-
      Places ramucirumab in the licensed second-line position, alongside the other
      targeted agents curated in this entry.

- name: Breast Surveillance for Female CDH1 Carriers
  action_category: SCREENING
  therapeutic_modality: DEVICE
  description: >-
    Lobular breast cancer is the second tumour of hereditary diffuse gastric cancer, so
    gastric risk management alone is insufficient for female germline CDH1 carriers. The
    IGCLC offers annual breast surveillance as one of the two acceptable strategies for
    managing that risk (the other being risk-reducing mastectomy, curated separately
    below). Recorded as a distinct clinical action because it is co-equal in stakes with
    the gastric recommendation and is easily overlooked once prophylactic gastrectomy
    has been addressed.
  treatment_term:
    preferred_term: Cancer Screening
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LBC risk should be managed with either annual surveillance or bilateral risk-reducing mastectomy (BRRM)."
    explanation: >-
      The IGCLC recommendation establishing annual surveillance as one of the two
      acceptable strategies for the breast arm of HDGC risk management.

- name: Risk-Reducing Bilateral Mastectomy for Female CDH1 Carriers
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Bilateral risk-reducing mastectomy is the surgical alternative to annual breast
    surveillance for female germline CDH1 carriers, and is the breast counterpart of
    prophylactic total gastrectomy: it removes the at-risk epithelial compartment in
    which the germline first hit is present. Modelled as its own THERAPEUTIC/SURGERY
    treatment rather than folded into the surveillance entry, matching the existing
    pattern in `Hereditary_Breast_and_Ovarian_Cancer_Syndrome`, `Cowden_Syndrome` and
    `Li-Fraumeni_Syndrome`, so that a query for surgical prophylaxis in CDH1 carriers
    returns it.
  treatment_term:
    preferred_term: Prophylactic Mastectomy
    term:
      id: NCIT:C94445
      label: Prophylactic Mastectomy
  target_mechanisms:
  - target: CDH1 Inactivation and E-cadherin Loss
    treatment_effect: INHIBITS
    description: >-
      Removes the at-risk breast epithelial compartment carrying the germline CDH1
      first hit, pre-empting the somatic second hit that would produce lobular breast
      carcinoma.
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LBC risk should be managed with either annual surveillance or bilateral risk-reducing mastectomy (BRRM)."
    explanation: >-
      The IGCLC recommendation establishing bilateral risk-reducing mastectomy as the
      surgical option for the breast arm of HDGC risk management.

- name: Perioperative FLOT Chemotherapy
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Fluorouracil, leucovorin, oxaliplatin and docetaxel given before and after
    gastrectomy for fit patients with locally advanced resectable gastric or
    gastroesophageal junction adenocarcinoma. Established as the Western standard by
    FLOT4, which reported a median overall survival of 50 months versus 35 months
    against the prior ECF/ECX standard (hazard ratio 0.77).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fluorouracil
      term:
        id: CHEBI:46345
        label: 5-fluorouracil
    - preferred_term: oxaliplatin
      term:
        id: CHEBI:31941
        label: oxaliplatin
    - preferred_term: leucovorin
      term:
        id: CHEBI:15640
        label: 5-formyltetrahydrofolic acid
    - preferred_term: docetaxel
      term:
        id: CHEBI:4672
        label: docetaxel anhydrous
  regimen_term:
    preferred_term: FLOT regimen
    term:
      id: NCIT:C160565
      label: FLOT Regimen
  evidence:
  - reference: PMID:30982686
    reference_title: "Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall survival was increased in the FLOT group compared with the ECF/ECX group"
    explanation: >-
      The FLOT4 primary result establishing perioperative FLOT as the standard of care.
  - reference: PMID:30982686
    reference_title: "Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX."
    explanation: >-
      The authors' interpretation, defining the indication as curated here.
- name: Trastuzumab for HER2-Positive Disease
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Anti-HER2 monoclonal antibody added to first-line fluoropyrimidine-platinum
    chemotherapy for HER2-overexpressing or HER2-amplified advanced gastric or
    gastroesophageal junction adenocarcinoma. The ToGA trial was the first demonstration
    that a targeted agent improves survival in this disease (median overall survival 13.8
    versus 11.1 months). Trastuzumab deruxtecan is an important later-line option after
    trastuzumab exposure. See `HER2_Positive_Gastric_Cancer` for the deeper treatment
    curation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trastuzumab
      term:
        id: NCIT:C1647
        label: Trastuzumab
  target_mechanisms:
  - target: Receptor Tyrosine Kinase Amplification
    treatment_effect: INHIBITS
    description: >-
      Binds the amplified HER2 receptor, blocking its ERBB2 signalling output. Note the
      target is the RTK amplification node, not the upstream chromosomal instability -
      trastuzumab does not correct aneuploidy.
  evidence:
  - reference: PMID:20728210
    reference_title: "Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median overall survival was 13.8 months (95% CI 12-16) in those assigned to trastuzumab plus chemotherapy compared with 11.1 months (10-13) in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60-0.91; p=0.0046)."
    explanation: >-
      The ToGA primary survival result quantifying HER2-directed benefit.
  - reference: PMID:20728210
    reference_title: "Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer."
    explanation: >-
      Establishes the standard-of-care status of the HER2-directed indication.
- name: Zolbetuximab for CLDN18.2-Positive HER2-Negative Disease
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Chimeric IgG1 monoclonal antibody against claudin-18 isoform 2, added to mFOLFOX6 in
    the first line for CLDN18.2-positive, HER2-negative advanced disease. It kills
    CLDN18.2-expressing tumour cells by antibody- and complement-dependent cytotoxicity.
    The therapeutic window exists because normal CLDN18.2 expression is restricted to
    short-lived differentiated gastric mucosal epithelium. Nausea and vomiting are
    prominent infusion-related toxicities.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zolbetuximab
      term:
        id: NCIT:C85475
        label: Zolbetuximab
  evidence:
  - reference: PMID:37068504
    reference_title: "Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6"
    explanation: >-
      The SPOTLIGHT interpretation establishing efficacy on both progression-free and
      overall survival.
  - reference: PMID:37068504
    reference_title: "Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo"
    explanation: >-
      Confirms the progression-free survival benefit of the CLDN18.2-directed indication.
- name: PD-1 Checkpoint Blockade (Pembrolizumab, Nivolumab)
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Anti-PD-1 antibodies added to first-line chemotherapy for HER2-negative advanced
    disease, with eligibility gated on PD-L1 combined positive score and with the largest
    benefit in MSI-high/dMMR and high-CPS tumours. KEYNOTE-859 reported a significant
    overall survival improvement in the intention-to-treat population (12.9 versus 11.5
    months, hazard ratio 0.78) that widened at higher CPS. Pembrolizumab is also added to
    trastuzumab plus chemotherapy in eligible PD-L1-positive HER2-positive disease.
    Immune-related adverse events are the characteristic toxicity class.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
    - preferred_term: nivolumab
      term:
        id: NCIT:C68814
        label: Nivolumab
  target_mechanisms:
  - target: Tumor Immune Evasion and Checkpoint Engagement
    treatment_effect: INHIBITS
    description: >-
      Blocks PD-1 on tumour-infiltrating T cells, releasing the checkpoint brake imposed
      by tumour PD-L1.
  evidence:
  - reference: PMID:37875143
    reference_title: "Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median overall survival was longer in the pembrolizumab group than in the placebo group in the ITT population"
    explanation: >-
      The KEYNOTE-859 primary overall survival result demonstrating checkpoint-blockade
      benefit.
  - reference: PMID:37875143
    reference_title: "Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pembrolizumab with chemotherapy might be a first-line treatment option for patients with locally advanced or metastatic HER2-negative gastric or gastro-esophageal junction adenocarcinoma."
    explanation: >-
      Defines the first-line HER2-negative indication curated here.
- name: Bemarituzumab for FGFR2b-Overexpressing Disease
  action_category: THERAPEUTIC
  therapeutic_modality: MONOCLONAL_ANTIBODY
  description: >-
    Afucosylated humanised monoclonal antibody against the FGFR2b isoform, added to
    mFOLFOX6 in FGFR2b-selected disease. The randomised phase 2 FIGHT study did not meet
    statistical significance for progression-free survival (9.5 versus 7.4 months, hazard
    ratio 0.68, p=0.073) but showed promising activity, and confirmatory phase 3 trials
    followed. Investigational rather than standard of care. A distinctive and
    dose-limiting on-target toxicity reported in the FIGHT safety analysis is corneal
    disorder, occurring as a grade 3 or worse event in 24% of bemarituzumab recipients
    and in none of the placebo group.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bemarituzumab
      term:
        id: NCIT:C120040
        label: Bemarituzumab
  target_mechanisms:
  - target: Receptor Tyrosine Kinase Amplification
    treatment_effect: INHIBITS
    description: >-
      Blocks the FGFR2b receptor tyrosine kinase amplified/overexpressed in a subset of
      CIN-class tumours.
  evidence:
  - reference: PMID:36244398
    reference_title: "Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "median progression-free survival was 9·5 months (95% CI 7·3-12·9) in the bemarituzumab group and 7·4 months (5·8-8·4) in the placebo group"
    explanation: >-
      Quantifies the efficacy signal. Support is PARTIAL because the difference did not
      reach statistical significance, which is why the entry frames bemarituzumab as
      investigational rather than standard of care.
  - reference: PMID:36244398
    reference_title: "Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this exploratory phase 2 study, despite no statistically significant improvement in progression-free survival, treatment with bemarituzumab showed promising clinical efficacy."
    explanation: >-
      The authors' own interpretation, which is the basis for the investigational framing
      and for the confirmatory phase 3 programme noted in the description.
- name: Endoscopic Submucosal Dissection for Early Gastric Cancer
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    En-bloc endoscopic resection of selected superficial lesions confined to the mucosa
    with negligible nodal risk, achieving cure while preserving the stomach. Applies to
    early gastric cancer meeting size, depth, differentiation and ulceration criteria -
    essentially a Correa-route intervention, since it presupposes a discrete
    intestinal-type lesion rather than diffuse infiltration.
  treatment_term:
    preferred_term: Endoscopic Submucosal Dissection
    term:
      id: NCIT:C157837
      label: Endoscopic Submucosal Dissection
  target_mechanisms:
  - target: Intestinal-Type Invasive Adenocarcinoma
    treatment_effect: INHIBITS
    description: >-
      Physically removes the intramucosal carcinoma before it can invade deeper or
      metastasise.
  evidence:
  - reference: PMID:39023829
    reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors"
    explanation: >-
      Guideline statement placing endoscopic resection as the standard for very early
      stage disease.
- name: Helicobacter pylori Screen-and-Treat (Primary Prevention)
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Population-level detection and eradication of H. pylori, the leading supportable
    gastric cancer prevention strategy in intermediate- and high-incidence regions.
    Eradication is most effective before advanced atrophy and intestinal metaplasia
    develop - the mechanistic reason the intervention window is early in the Correa
    cascade. It also prevents peptic ulcer disease and gastric MALT lymphoma. A
    recognised trade-off is increased population antibiotic use. Note this treats the
    trigger; it does not treat established cancer.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Helicobacter pylori Chronic Active Gastritis
    treatment_effect: INHIBITS
    description: >-
      Eliminates the persistent inflammatory stimulus that initiates the Correa cascade.
  evidence:
  - reference: PMID:39237127
    reference_title: "Where are we with gastric cancer screening in Europe in 2024?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the screen and treat strategy for Helicobacter pylori (H. pylori) seems to be the most appropriate for Europe"
    explanation: >-
      Establishes H. pylori screen-and-treat as the leading population prevention
      strategy.
  - reference: PMID:39237127
    reference_title: "Where are we with gastric cancer screening in Europe in 2024?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It has to be noted that increased use of antibiotics would be associated with this strategy."
    explanation: >-
      Documents the antibiotic-stewardship trade-off of the strategy, curated as a caveat.
- name: Endoscopic Surveillance in Hereditary and Precancerous Settings
  action_category: SCREENING
  therapeutic_modality: DEVICE
  description: >-
    Upper endoscopy with protocol biopsies, used in two distinct settings: surveillance of
    advanced precancerous gastric conditions (extensive atrophic gastritis, intestinal
    metaplasia, dysplasia) along the Correa route, and as an alternative to immediate
    prophylactic gastrectomy for selected germline CDH1 carriers in expert centres. In the
    HDGC setting its sensitivity is inherently imperfect because signet-ring-cell foci are
    small, submucosal and endoscopically inapparent.
  treatment_term:
    preferred_term: Gastroscopy
    term:
      id: NCIT:C16604
      label: Gastroscopy
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the growing capability of endoscopic and histological surveillance in HDGC"
    explanation: >-
      IGCLC recognition of endoscopic and histological surveillance as an increasingly
      capable option in HDGC.
- name: Genetic Counselling and Cascade Testing
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  description: >-
    Referral for genetic counselling is indicated for young-onset diffuse gastric cancer,
    a family history meeting HDGC criteria, bilateral or familial lobular breast cancer,
    Lynch-compatible MSI, or polyposis. Testing should use a hereditary gastric cancer
    panel covering CDH1, CTNNA1, the mismatch repair genes, APC, STK11, SMAD4, BMPR1A and
    TP53, including deletion/duplication analysis. Identification of a familial variant
    triggers cascade testing of at-risk relatives, which is what converts a diagnosis in
    one patient into prevention for the family.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38160327
    reference_title: "The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the guidelines offer detailed screening recommendations for hereditary gastric cancer"
    explanation: >-
      Guideline confirmation that hereditary gastric cancer screening is a defined
      component of gastric cancer care.

datasets:
- accession: https://portal.gdc.cancer.gov/projects/TCGA-STAD
  title: https://portal.gdc.cancer.gov/projects/TCGA-STAD
  description: >-
    The Cancer Genome Atlas stomach adenocarcinoma project (TCGA-STAD). Multi-platform
    molecular profiling (whole-exome sequencing, mRNA and miRNA expression, DNA
    methylation, copy number and reverse-phase protein arrays) of 295 primary gastric
    adenocarcinomas. This is the dataset from which the four-class EBV / MSI /
    genomically stable / chromosomal instability molecular taxonomy used throughout this
    entry was derived, and the primary resource for validating those class assignments.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS
  sample_count: 295
  publication: PMID:25079317
  evidence:
  - reference: PMID:25079317
    reference_title: "Comprehensive molecular characterization of gastric adenocarcinoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project."
    explanation: >-
      Establishes the dataset's identity, size (295 primary tumours) and multi-platform
      molecular scope.

classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:38572751
      reference_title: "Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "followed by colorectal (9.3%), liver (7.8%), female breast (6.9%), and stomach (6.8%) cancers"
      explanation: >-
        Gastric adenocarcinoma is a malignant neoplasm ranked among the leading causes of
        cancer death, placing it squarely in the oncology/haematology domain.
  icdo_morphology:
    classification_value: Adenocarcinoma
    notes: >-
      ICD-O-3 morphology 8140/3 (adenocarcinoma, NOS) for the general case, with
      8144/3 (adenocarcinoma, intestinal type) and 8490/3 (signet ring cell carcinoma)
      for the two Lauren poles, and 8145/3 for carcinoma, diffuse type. Topography C16
      (stomach).
    evidence:
    - reference: PMID:39023829
      reference_title: "SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Approximately 90% of GC are adenocarcinomas (Ac), which are subdivided into diffuse and intestinal (Lauren classification)"
      explanation: >-
        Supports the adenocarcinoma morphology assignment and the intestinal/diffuse
        morphologic split underlying the ICD-O subtype codes.

mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005036
      label: gastric adenocarcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      This entry is scoped exactly to the MONDO gastric adenocarcinoma concept - the
      histologic parent of the existing H. pylori-associated, HER2-positive,
      EBV-associated and metastatic gastric entries, none of which carries this term.

📚

References & Deep Research

References

PMID:25079317

Comprehensive molecular characterization of gastric adenocarcinoma.

No top-level findings curated for this source.

PMID:32758476

Hereditary diffuse gastric cancer: updated clinical practice guidelines.

No top-level findings curated for this source.

Deep Research

Falcon ▸

Gastric Adenocarcinoma: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 43 citations 2026-08-01T07:09:46.134360

Gastric Adenocarcinoma: Comprehensive Disease-Characteristics Report

Executive summary

Gastric adenocarcinoma is a malignant gland-forming epithelial neoplasm of the stomach and constitutes approximately 90% of gastric cancers. It is not one disease biologically: intestinal, diffuse, and mixed histologies coexist with Epstein–Barr virus-positive (EBV+), microsatellite-instability (MSI), genomically stable (GS), and chromosomal-instability (CIN) molecular classes. Its principal preventable cause is chronic Helicobacter pylori infection; inherited disease is uncommon but clinically important, particularly autosomal-dominant CDH1/CTNNA1-associated hereditary diffuse gastric cancer (HDGC). Contemporary management is stage- and biomarker-dependent and requires HER2, MMR/MSI, PD-L1, and increasingly CLDN18.2 testing. The 2023–2024 literature emphasizes population H. pylori eradication, precision systemic therapy, and single-cell/spatial dissection of tumor heterogeneity. (wang2024thechinesesociety pages 7-8, lordick2024systemictherapyof pages 8-10, rivera2024seomgemcadttdclinicalguideline pages 1-2, sluis2024currentadvancesand pages 1-2)

The following table is a compact knowledge-base scaffold; the narrative below provides qualification and evidence.

Domain	Core facts	Suggested ontology terms	Key evidence
Identity / identifiers	Gastric adenocarcinoma is the dominant histologic form of stomach cancer; ~90% of gastric cancers are adenocarcinomas. MONDO:0005036. Disease-level knowledge here is derived mainly from aggregated literature/guidelines, not individual EHRs.	MONDO:0005036; MeSH: Stomach Neoplasms / Adenocarcinoma; ICD-11 gastric carcinoma terms	(rivera2024seomgemcadttdclinicalguideline pages 1-2)
Histology / classification	Lauren types: intestinal, diffuse, mixed. Early gastric cancer is limited to mucosa/submucosa; advanced disease invades muscularis propria or deeper. WHO/Lauren classification remains standard pathology framework.	NCIT gastric adenocarcinoma; HPO: gastric adenocarcinoma; UBERON: stomach	(wang2024thechinesesociety pages 7-8)
Molecular classes	TCGA framework: EBV-positive, MSI, genomically stable (GS), chromosomal instability (CIN). EBV/MSI enrich for immune sensitivity; GS often overlaps diffuse-type biology; CIN often associates with RTK amplifications.	NCIT: Epstein-Barr virus positive tumor; MSI-high; chromosomal instability	(OpenTargets Search: gastric adenocarcinoma, lordick2024systemictherapyof pages 8-10)
Major etiologies / risks	Major causes/risk factors: Helicobacter pylori, smoking, high-salt/processed meat diets, low fruit/vegetable intake, atrophic gastritis, autoimmune gastritis; obesity/GERD more relevant for proximal/GEJ disease; EBV contributes in a subset.	CHEBI: sodium chloride; NCBITaxon: Helicobacter pylori; HPO: chronic gastritis, intestinal metaplasia	(rivera2024seomgemcadttdclinicalguideline pages 1-2, leja2024wherearewe pages 3-4)
Protective / preventive factors	H. pylori eradication lowers gastric cancer incidence; benefit is greatest before advanced precancerous lesions but may still extend later in life. Population “screen-and-treat” is the leading prevention strategy in many regions.	NCIT: Helicobacter pylori eradication therapy; preventive screening	(leja2024wherearewe pages 6-6, leja2024wherearewe pages 3-3)
Germline genes	Hereditary diffuse gastric cancer is chiefly due to CDH1 and less often CTNNA1; autosomal dominant. CDH1 loss usually needs a second hit, commonly promoter hypermethylation. APC underlies GAPPS, a distinct hereditary gastric neoplasia syndrome.	HGNC: CDH1, CTNNA1, APC; MONDO hereditary diffuse gastric adenocarcinoma	(sluis2024currentadvancesand pages 1-2, lim2023currentadvancesin pages 2-4, pereira2025hereditarydiffusegastric pages 2-4, OpenTargets Search: gastric adenocarcinoma)
Major somatic drivers	Recurrently implicated genes/pathways include TP53, ARID1A, KRAS, RHOA, PIK3CA, RNF43, KMT2D, SMAD4, ERBB2 and angiogenic signaling via KDR/VEGFR2. HER2 amplification is a key actionable alteration; RHOA is enriched in diffuse/GS disease.	HGNC: TP53, ARID1A, KRAS, RHOA, PIK3CA, ERBB2, RNF43, KMT2D, SMAD4, KDR	(OpenTargets Search: gastric adenocarcinoma, lordick2024systemictherapyof pages 8-10)
Mechanisms / pathways	Carcinogenesis reflects interaction of microbial inflammation, epithelial injury, stem/progenitor DNA damage, Wnt/MAPK/PI3K signaling, EMT/invasion, and immune evasion. In HDGC, E-cadherin loss disrupts adhesion and spindle orientation; in experimental systems H. pylori plus Apc loss augments DNA damage in gastric stem/progenitor cells.	GO: cell adhesion, Wnt signaling, MAPK cascade, PI3K-AKT signaling, epithelial to mesenchymal transition; CL: gastric epithelial cell, macrophage, CD8-positive T cell	(sluis2024currentadvancesand pages 1-2, lim2023currentadvancesin pages 2-4, deng2023singlecelltranscriptomesequencing pages 4-5)
Clinical phenotypes	Common manifestations include dyspepsia, weight loss, early satiety, abdominal pain, iron-deficiency anemia, bleeding, obstruction, and metastatic symptoms. Diffuse/signet-ring cancers may infiltrate the wall with less obvious gland formation.	HPO: Abdominal pain, Early satiety, Weight loss, Iron deficiency anemia, Gastrointestinal hemorrhage, Gastric outlet obstruction	(wang2024thechinesesociety pages 7-8, rivera2024seomgemcadttdclinicalguideline pages 1-2)
Anatomy affected	Primary organ: stomach, especially mucosa/glandular epithelium; proximal/GEJ and distal/antral patterns differ epidemiologically. Common secondary sites include lymph nodes, peritoneum, liver, lung, and ovary/adnexa; peritoneal spread is a major complication.	UBERON: stomach, gastric mucosa, lymph node, liver, peritoneum, lung; CL: gastric epithelial cell	(rivera2024seomgemcadttdclinicalguideline pages 1-2)
Diagnostics / biomarkers	Diagnostic gold standard: upper endoscopy with biopsy reviewed by experienced pathology; multiple biopsies improve accuracy. Staging uses CT chest/abdomen/pelvis; EUS refines depth/nodes; laparoscopy with peritoneal lavage detects occult peritoneal disease. Core biomarkers: HER2, MMR/MSI, PD-L1 CPS, CLDN18.2; NGS and liquid biopsy are emerging/investigational in guidelines.	NCIT: Endoscopy, Biopsy, Endoscopic ultrasonography, Computed tomography, Diagnostic laparoscopy; HGNC/biomarkers: ERBB2, PD-L1(CD274), CLDN18, MMR genes	(wang2024thechinesesociety pages 4-5, rivera2024seomgemcadttdclinicalguideline pages 1-2, gullo2020precancerouslesionsof pages 6-8)
Treatment by stage / biomarker	Very early disease: EMR/ESD in selected superficial lesions. Resectable locally advanced disease: gastrectomy plus perioperative chemotherapy (FLOT in many Western settings) or adjuvant strategies in East Asia. Metastatic disease: fluoropyrimidine-platinum backbone, adding trastuzumab for HER2+, pembrolizumab/nivolumab-based therapy by PD-L1 or MSI status, and zolbetuximab for CLDN18.2+ HER2-negative disease; anti-VEGFR2 strategies are standard in later lines in many regions.	NCIT: Gastrectomy, Endoscopic mucosal resection, Endoscopic submucosal dissection, FLOT regimen, Trastuzumab, Pembrolizumab, Nivolumab, Zolbetuximab, Ramucirumab	(lordick2024systemictherapyof pages 8-10, wang2024thechinesesociety pages 4-5, rivera2024seomgemcadttdclinicalguideline pages 1-2)
Prevention / screening	East Asian programs support endoscopic screening; Korea screens adults ≥40 every 2 years and Japan uses endoscopy from age 50. China’s county-level endoscopic program was associated with a 15% mortality decrease. In Europe, organized population H. pylori screen-and-treat is the main currently supportable strategy, while direct endoscopic screening evidence remains less mature.	NCIT: Mass screening, Endoscopy, Helicobacter pylori test-and-treat	(mok2024racialdisparitiesof pages 7-8, leja2024wherearewe pages 6-6, mok2024racialdisparitiesof pages 5-7, leja2024wherearewe pages 6-7)
Prognosis	Prognosis depends strongly on stage, TNM class, age, surgery, and treatment response. Advanced/metastatic gastric cancer still has poor median survival, often <12 months with conventional chemotherapy alone, though biomarker-guided immunotherapy/targeted therapy has improved outcomes. In high-risk Chinese older cohorts, 3-year OS declined from 58.5% to 34.4% across 2010-2019, underscoring ongoing mortality burden.	HPO: reduced survival; NCIT: overall survival, progression-free survival	(burz2024prognosisandtreatment pages 2-4, lordick2024systemictherapyof pages 8-10)
Epidemiology	Gastric cancer burden is geographically concentrated in East Asia and is higher in males and older adults. In Asia (GLOBOCAN 2020), ASIR was 14.3/100,000 overall, 20.4 in males and 8.7 in females; ASMR was 10.0 overall.	NCIT: incidence, mortality; demographic descriptors	(mok2024racialdisparitiesof pages 7-8, leja2024wherearewe pages 6-6)
Model systems	Key translational models include patient-derived organoids, gastric organoid infection systems, PDX models, and genetically engineered mouse/organoid HDGC models. Single-cell/spatial studies profile epithelial, fibroblast, macrophage, B-cell, neutrophil, and CD8 T-cell states; experimentally supported axes include IL1B-IL1R2, CXCL5-CXCR2, and CCL28-CCR10. Main limitations: partial loss of native microenvironment, biomarker heterogeneity, and incomplete capture of long-term evolution.	NCIT: Patient-derived xenograft model, Organoid, Single-cell RNA sequencing, Spatial transcriptomics; CL: macrophage, fibroblast, B cell, neutrophil, CD8-positive T cell	(xu2024singlecellrnasequencing pages 9-11, liang2024theburgeoningspatial pages 19-20, deng2023singlecelltranscriptomesequencing pages 4-5)

Table: This compact table summarizes the core disease-knowledge domains for gastric adenocarcinoma, including classification, etiology, genetics, clinical features, diagnostics, treatment, prevention, prognosis, and models. It is designed as a concise scaffold for populating a disease knowledge base with ontology suggestions and evidence anchors.

1. Disease information

Definition and category. Gastric adenocarcinoma is a primary malignant epithelial tumor showing glandular differentiation arising in gastric mucosa. It belongs to digestive-system malignancies and epithelial adenocarcinomas. “Gastric cancer” is broader and also includes lymphoma, gastrointestinal stromal tumor, neuroendocrine neoplasm, and rarer nonepithelial tumors; therefore, the terms should not be treated as perfectly synonymous.

Identifiers and synonyms. Recommended identifier: MONDO:0005036. Useful mappings include MeSH Stomach Neoplasms plus Adenocarcinoma; ICD-10-CM C16.0–C16.9, coded by gastric site; and ICD-11 malignant neoplasm of stomach categories. Synonyms include gastric adenocarcinoma, stomach adenocarcinoma, gastric carcinoma, adenocarcinoma type, and TCGA shorthand STAD. More specific MONDO entities include gastric intestinal-type adenocarcinoma, signet-ring-cell gastric adenocarcinoma, and hereditary diffuse gastric adenocarcinoma. Open Targets recognizes MONDO:0005036 and connects it to CDH1, ERBB2, TP53, KDR, ARID1A, KRAS, RHOA, CTNNA1, PIK3CA, RNF43, KMT2D, and SMAD4. (OpenTargets Search: gastric adenocarcinoma)

Classification. Lauren classification separates intestinal tumors—atypical gland formation often arising through atrophy and intestinal metaplasia—from diffuse tumors composed of poorly cohesive infiltrating cells, sometimes signet-ring cells, and mixed tumors. “Early gastric cancer” is confined to mucosa or submucosa irrespective of nodes; advanced cancer invades muscularis propria or deeper. Reporting follows WHO histology and AJCC/UICC TNM, eighth edition. (wang2024thechinesesociety pages 7-8)

Data provenance. This report represents aggregated disease-level evidence from publications, guidelines, registries, ClinicalTrials.gov, and Open Targets. It is not an extraction from individual EHRs. Some cited studies do analyze patient-level biopsies or trial participants, but only published aggregate findings are presented.

2. Etiology, risks, protection, and gene–environment interaction

Causal and environmental factors

H. pylori is the dominant cause of non-cardia intestinal-type disease. The causal chain is chronic infection → active gastritis → multifocal atrophy → intestinal metaplasia → dysplasia → invasive adenocarcinoma, with bacterial virulence factors, host inflammation, diet, and smoking modifying progression. A 2024 European review states that close to 90% of non-cardia cases are related to H. pylori. Other established or probable factors include tobacco smoking, high salt and salt-preserved foods, processed meat, low fruit/vegetable intake, older age, male sex, family history, gastric atrophy, pernicious anemia/autoimmune gastritis, prior gastric surgery, and some occupational or socioeconomic exposures. Obesity and gastroesophageal reflux are more strongly linked to cardia/GEJ adenocarcinoma. EBV is a tumor-associated infectious agent in a minority of cancers, rather than a transmissible cancer. (rivera2024seomgemcadttdclinicalguideline pages 1-2, leja2024wherearewe pages 6-6, leja2024wherearewe pages 3-4)

Autoimmune atrophic gastritis damages oxyntic mucosa and creates achlorhydria, hypergastrinemia, iron/B12 deficiency, metaplasia, and increased gastric malignancy risk. Alcohol associations are less consistent than those for smoking, salt, and H. pylori and may vary by tumor site.

Genetic susceptibility

Most cases are sporadic and multifactorial. Approximately 10% show familial clustering, while recognized high-penetrance hereditary syndromes account for roughly 1–3%. Important syndromes include HDGC (CDH1, CTNNA1), Lynch syndrome (MMR genes), familial adenomatous polyposis and gastric adenocarcinoma and proximal polyposis of the stomach (APC promoter 1B variants), Peutz–Jeghers syndrome (STK11), juvenile polyposis (SMAD4/BMPR1A), and Li–Fraumeni syndrome (TP53). Open Targets separately associates APC with GAPPS. (OpenTargets Search: gastric adenocarcinoma, lim2023currentadvancesin pages 1-2)

Protective factors

The strongest intervention-level protective evidence is eradication of H. pylori, preferably before extensive atrophy/metaplasia develops. Smoking cessation, reduced salt-preserved/processed food intake, healthy weight, and diets rich in fresh produce are reasonable risk-reduction measures, although their evidence is less intervention-specific than eradication. No approved vaccine prevents H. pylori or gastric cancer. (leja2024wherearewe pages 6-6, leja2024wherearewe pages 3-4, leja2024wherearewe pages 3-3)

Gene–environment interaction

Inherited or polygenic susceptibility can amplify microbial injury. CDH1 deficiency lowers epithelial cohesion; inflammatory and epigenetic second hits can then promote invasion. Experimentally, H. pylori causes transcription-dependent DNA damage and replication stress in LGR5-positive antral and Troy-positive corpus stem/progenitor cells; Apc inactivation and constitutive Wnt-driven hyperproliferation aggravate this injury, whereas Trp53 or Smad4 loss did not do so in that model. This is mechanistic mouse-organoid evidence, not proof of an identical quantitative effect in humans.

3. Phenotypes and quality-of-life effects

Onset is usually insidious in later adulthood; early disease is often asymptomatic. Frequencies vary strongly by stage and population, so universal percentages are inappropriate.

Dyspepsia/epigastric pain—variable, often mild initially and progressive; suggested HPO Abdominal pain (HP:0002027) and dyspepsia term where available.
Early satiety, postprandial fullness, nausea/vomiting—especially with reduced gastric compliance or outlet disease; suggested HPO Early satiety, Nausea (HP:0002018), Vomiting (HP:0002013).
Unintentional weight loss, anorexia, fatigue/cachexia—common in advanced disease and major determinants of function; suggested Weight loss (HP:0001824), Feeding difficulties, Fatigue (HP:0012378).
Occult/overt bleeding and iron-deficiency anemia—laboratory and clinical phenotypes; suggested Gastrointestinal hemorrhage (HP:0002239), Iron deficiency anemia (HP:0001891).
Dysphagia—particularly cardia/GEJ lesions; suggested Dysphagia (HP:0002015).
Gastric outlet obstruction—late local complication with vomiting/dehydration; suggested HPO gastric outlet obstruction.
Metastatic manifestations—ascites/peritoneal carcinomatosis, hepatomegaly or liver dysfunction, pleural symptoms, nodal disease, and ovarian Krukenberg metastasis. Diffuse cancers often seed the peritoneum.

Cancer symptoms, gastrectomy, chemotherapy toxicity, nutritional deficiencies, altered body image, fear of recurrence, and financial stress impair physical, emotional, and social quality of life. After total gastrectomy, lifelong small frequent meals, weight loss, dumping, reflux, anemia, and B12 replacement may be required. Guidelines consequently support multidisciplinary nutrition, psycho-oncology, symptom control, and palliative care. (burz2024prognosisandtreatment pages 2-4, rivera2024seomgemcadttdclinicalguideline pages 1-2)

4. Genetic and molecular information

Germline disease

CDH1 encodes E-cadherin and CTNNA1 encodes α-catenin; both are components of adherens junctions. HDGC is autosomal dominant with incomplete, family-dependent, age-dependent penetrance. Pathogenic CDH1 variants include nonsense, frameshift, splice-site, and deletions; truncating variants are generally easier to classify than missense variants, which often remain VUS without functional/segregation evidence. The second somatic hit is frequently CDH1 promoter hypermethylation (reported in 32.1% of lesions in one synthesis), followed by loss of heterozygosity (25%) or somatic mutation. CTNNA1 accounts for fewer than 2% of HDGC families and appears lower penetrance. (sluis2024currentadvancesand pages 1-2, lim2023currentadvancesin pages 2-4)

Penetrance estimates have changed with ascertainment. Older selected-family estimates were approximately 42% in men and 33% in women, whereas a 2024 review incorporating less selected families estimated lifetime advanced diffuse-gastric-cancer risk at 13–19%. These values are not contradictory measurements of one population; they demonstrate ascertainment and variant-specific uncertainty. Lobular breast-cancer risk is also elevated in female CDH1 carriers. (sluis2024currentadvancesand pages 1-2, gullo2020precancerouslesionsof pages 14-15)

Pathogenic germline alleles are rare in population databases; a true high-penetrance pathogenic variant is generally expected to be absent or extremely rare in gnomAD. Variant classification must use ClinVar/ClinGen expert curation and ACMG/AMP criteria rather than frequency alone. Genetic anticipation and repeat expansions are not characteristic. Founder variants exist in some families/populations, but no single global carrier frequency applies.

Somatic alterations and chromosomal abnormalities

Prominent alterations include loss-of-function TP53, ARID1A, RNF43, SMAD4, and chromatin-regulator mutations; activating or amplifying events in ERBB2/HER2, KRAS, PIK3CA, MET, FGFR2, and angiogenic pathways; and RHOA mutation or CLDN18–ARHGAP fusions in diffuse/GS cancers. CIN tumors show aneuploidy and focal receptor-tyrosine-kinase amplification; MSI tumors accumulate frameshift mutations because of MMR deficiency; EBV+ tumors often show PIK3CA mutation, immune signaling, and extensive promoter methylation. Open Targets provides integrated human genetic, somatic, and therapeutic evidence for the principal targets. (OpenTargets Search: gastric adenocarcinoma)

Approximate actionable frequencies vary by assay, geography, and stage: HER2 5–25%; MSI-H/dMMR 8–25% overall but lower in metastatic cohorts; FGFR1/3 amplification ~2%; homologous-recombination-deficiency signatures 7–12%; KRAS G12C ~1%; MET amplification 2–11%; and PIK3CA alteration ~3.5% in one contemporary summary. These are cohort estimates, not universal prevalence. (lordick2024systemictherapyof pages 8-10, rivera2024seomgemcadttdclinicalguideline pages 1-2)

Epigenetics and modifiers

Key epigenetic events include CpG-island methylation induced by chronic inflammation, CDH1 promoter methylation, MLH1 methylation in sporadic MSI cancer, and EBV-associated hypermethylation. ARID1A/KMT2D disruption remodels chromatin. Putative modifier effects from inflammatory, detoxification, and DNA-repair polymorphisms have been reported, but few are clinically actionable.

5. Environmental and infectious information

Relevant non-genetic exposures comprise H. pylori; smoking; high dietary sodium/nitrosated or preserved food; low produce intake; obesity/GERD for proximal tumors; chronic gastric inflammation; and healthcare disparities that delay detection. Ionizing radiation is not a dominant population cause, although prior radiotherapy can rarely contribute. H. pylori is NCBI Taxonomy 210; EBV/human gammaherpesvirus 4 is NCBI Taxonomy 10376. Neither gastric adenocarcinoma nor its EBV-associated subtype is contagious or zoonotic.

6. Mechanism and pathophysiology

Causal chains

Intestinal pathway: H. pylori and diet/smoking → epithelial injury and NF-κB/cytokine inflammation → atrophy/hypochlorhydria → intestinal metaplasia/dysplasia → TP53/CIN or MSI evolution → invasion and metastasis.
Diffuse/HDGC pathway: germline plus somatic loss of CDH1/CTNNA1 → defective adherens junctions, polarity, spindle orientation, and anoikis control → microscopic signet-ring foci → additional Wnt/Notch/RHOA and stromal changes → infiltrative linitis-plastica-like cancer. Tiny pT1a signet-ring foci occur in most prophylactic gastrectomies, but which foci progress is unpredictable. (sluis2024currentadvancesand pages 1-2, lim2023currentadvancesin pages 2-4, gullo2020precancerouslesionsof pages 15-17)
EBV pathway: latent viral infection → epigenetic reprogramming and immune-checkpoint-rich microenvironment → EBV+ adenocarcinoma.
Metastatic pathway: EMT-like programs, extracellular-matrix remodeling, angiogenesis through VEGF–VEGFR2, immune escape, and peritoneal survival promote dissemination.

Suggested GO terms include cell–cell adhesion (GO:0098609), canonical Wnt signaling (GO:0060070), MAPK cascade (GO:0000165), PI3K signaling, inflammatory response (GO:0006954), DNA-damage response (GO:0006974), angiogenesis (GO:0001525), EMT (GO:0001837), apoptosis, and immune-response regulation. Relevant CL concepts include gastric epithelial cell, mucous neck/foveolar cell, chief cell, parietal cell, LGR5+ epithelial stem cell, fibroblast, endothelial cell, macrophage, neutrophil, B/plasma cell, and CD8+ T cell.

Molecular profiling and advanced technologies

Single-cell and spatial work demonstrates that bulk “gastric cancer” averages over malignant epithelial states, fibroblasts/myofibroblasts, endothelial cells, macrophages, neutrophils, B/plasma cells, and heterogeneous T cells. Approximately 200,000 cells from 48 samples in 31 patients were combined with spatial profiling of 156 regions in one landmark program; another 2023 analysis integrated spatial transcriptomics, metabolomics, and lipidomics from seven male patients. (liang2024theburgeoningspatial pages 19-20)

Recent findings include protumor neutrophil recruitment through CXCL5–CXCR2, CD8 exhaustion associated with LAG3, chemotherapy-associated expansion of fibroblast/myofibroblast states, tumor–macrophage IL1B–IL1R2 signaling, and strong immune sensitivity in some MSI-H tumors with high TMB, diverse TCR repertoires, and abundant T-cell infiltration. A gastric-cancer cell/B-cell analysis implicated CCL28–CCR10 recruitment of IgA plasma cells. These findings are promising biological hypotheses, but most are not yet validated clinical tests. (xu2024singlecellrnasequencing pages 9-11, deng2023singlecelltranscriptomesequencing pages 4-5, xu2024singlecellrnasequencing pages 13-14)

Direct abstract-level conclusion: a 2024 single-cell review states that scRNA-seq provides “unprecedented insights into the complicated biological composition and characteristics of TME,” while spatial transcriptomics captures local communication networks. (Publication: September 2024; https://doi.org/10.1007/s00262-024-03820-4.) (xu2024singlecellrnasequencing pages 9-11)

7. Anatomical structures affected

The primary site is the stomach—cardia, fundus, body, antrum, pylorus, lesser/greater curvature, or overlapping/unspecified sites—with origin in glandular mucosal epithelium. Suggested anatomy terms are UBERON stomach, gastric mucosa, gastric gland, cardia, fundus, body, antrum, and pylorus. Disease is not lateralized.

Local progression crosses submucosa, muscularis propria, subserosa, and serosa and may invade esophagus, duodenum, pancreas, spleen, colon, or abdominal wall. Secondary sites include perigastric and distant lymph nodes, peritoneum/omentum, liver, lung, bone, and ovaries. Subcellular compartments implicated include plasma-membrane adherens/tight junctions, nucleus/chromatin, mitochondria, ER, and extracellular matrix.

8. Temporal development

Onset is generally adult/geriatric, chronic, and insidious; young-onset cases are enriched for diffuse histology and hereditary evaluation. The Correa sequence may evolve over years to decades. TNM stage I–IV is the principal clinical course framework. Progression is variable but untreated invasive disease is progressive, with lymphatic, hematogenous, or transcoelomic spread.

The critical intervention windows are: eradicate H. pylori before advanced atrophy; detect and endoscopically remove eligible intramucosal lesions; undertake curative gastrectomy before metastatic spread; and identify actionable biomarkers before systemic therapy. Remission is treatment-induced rather than reliably spontaneous. Recurrence after curative-intent therapy is most often locoregional, peritoneal, or distant and generally occurs in the first several years, although late relapse is possible.

9. Inheritance and population epidemiology

HDGC is autosomal dominant with variable expressivity and incomplete, age-dependent penetrance. Germline mosaicism is not a common defining feature; consanguinity has no special role in this dominant syndrome. Cascade testing is appropriate after a pathogenic familial variant is identified. (sluis2024currentadvancesand pages 1-2, gullo2020precancerouslesionsof pages 14-15)

Population burden is highest in East Asia, parts of Eastern Europe, and Latin America; incidence rises steeply with age and is approximately twice as high in men in many populations. Asian GLOBOCAN 2020 estimates were an age-standardized incidence rate of 14.3/100,000 overall—20.4 in men and 8.7 in women—and mortality of 10.0/100,000 overall. Disease burden peaks after age 70. In a very-high-risk Chinese older population, incidence declined from 439.65 to 330.40 per 100,000 during 2010–2019, but hospital-cohort three-year OS declined from 58.5% to 34.4%, illustrating that regional registry estimates should not be generalized globally.

10. Diagnostics

Standard work-up. Upper endoscopy with multiple biopsies and expert WHO-based histopathology is the diagnostic gold standard; multiple samples can raise accuracy from about 70% to 98%. CT chest/abdomen/pelvis stages distant disease; EUS improves depth and regional-node assessment; MRI or FDG-PET/CT is selective. Diagnostic laparoscopy with washings is recommended for potentially resectable stage IB–III or cT3–4 disease at meaningful risk of occult peritoneal spread. Positive cytology is metastatic disease in major staging systems. (wang2024thechinesesociety pages 4-5, rivera2024seomgemcadttdclinicalguideline pages 1-2)

Pathology should report histotype, grade, Lauren type, depth, margins, lymphovascular/perineural invasion, regression after neoadjuvant therapy, and nodes—at least 16, preferably more than 30 for robust staging. (wang2024thechinesesociety pages 7-8)

Biomarkers. Test advanced disease for:

HER2/ERBB2: IHC followed by ISH for equivocal cases; obtain adequate tissue because expression is heterogeneous.
MMR/MSI: MLH1, PMS2, MSH2, MSH6 IHC and/or PCR/NGS.
PD-L1: combined positive score, assay- and jurisdiction-specific thresholds.
CLDN18.2: validated IHC for zolbetuximab eligibility.
Consider EBV-encoded RNA ISH, broad NGS, NTRK fusion, TMB, MET/FGFR2, and ctDNA in selected advanced cases/trials.

HER2 occurs in roughly 5–25% and MSI-H/dMMR in 8–25%, but prevalence depends on site, histology, ancestry, and stage. In a 536-patient advanced cohort, CLDN18.2 positivity was 57.6% at a ≥40% 2+ cutoff and 48.9% at a ≥70% cutoff; co-expression with PD-L1 was much less common. (lordick2024systemictherapyof pages 8-10, rivera2024seomgemcadttdclinicalguideline pages 1-2)

Routine serum CEA, CA19-9, and CA72-4 lack sufficient sensitivity/specificity for diagnosis or population screening, though trends may aid monitoring. ctDNA, extracellular-vesicle, proteomic, metabolomic, and AI-radiomic assays remain adjunctive or investigational. Guidelines explicitly describe NGS and liquid biopsy as emerging rather than replacements for tissue diagnosis. (wang2024thechinesesociety pages 4-5)

Genetic testing. Refer for counseling when HDGC criteria, young diffuse cancer, bilateral/familial lobular breast cancer, Lynch-compatible MSI, polyposis, or a strong family history is present. Start with a germline hereditary gastric-cancer panel including CDH1, CTNNA1, MMR genes, APC, STK11, SMAD4, BMPR1A, TP53 and other phenotype-directed genes; deletion/duplication analysis is essential. WES/WGS may help unresolved families but can increase VUS burden. CMA, karyotype, mitochondrial testing, and repeat-expansion testing are not routine diagnostic tests for gastric adenocarcinoma.

Differential diagnosis. Exclude gastric lymphoma, GIST, neuroendocrine neoplasm, metastatic breast/lung/melanoma, pancreaticobiliary invasion, benign ulcer, gastritis, and signet-ring mimics. In HDGC biopsies, globoid/vacuolated cells, xanthomatous cells, and autolysis can mimic signet-ring carcinoma. (gullo2020precancerouslesionsof pages 15-17)

11. Outcome and prognosis

Stage is the dominant predictor. Early mucosal cancers treated completely can have excellent long-term survival; metastatic disease remains usually incurable. Poor prognostic features include advanced T/N/M stage, peritoneal metastasis, poor performance status, malnutrition, diffuse/signet-ring phenotype in relevant settings, lymphovascular/perineural invasion, incomplete resection, and treatment resistance. MSI-H and EBV+ biology may predict immunotherapy sensitivity, while biomarker expression can vary spatially and over time.

Advanced gastric cancer historically had median survival under 12 months with conventional chemotherapy; HER2-, PD-1/PD-L1-, VEGFR2-, and CLDN18.2-directed therapies have incrementally improved outcomes in selected groups. Survivorship morbidity includes malnutrition, sarcopenia, dumping, B12/iron deficiency, neuropathy, fatigue, anxiety, and impaired social function. (burz2024prognosisandtreatment pages 2-4, lordick2024systemictherapyof pages 8-10)

12. Treatment

Localized disease

Very early eligible lesions: endoscopic mucosal resection or endoscopic submucosal dissection with en-bloc negative margins (NCIT: Endoscopic Mucosal Resection; Endoscopic Submucosal Dissection).
Resectable invasive disease: subtotal or total gastrectomy with appropriate lymphadenectomy, usually D2 in experienced centers (NCIT: Gastrectomy; Lymphadenectomy).
Western practice: perioperative FLOT—5-FU, leucovorin, oxaliplatin, docetaxel—for fit locally advanced patients.
East Asian practice: surgery followed by S-1 or platinum–fluoropyrimidine regimens is common after D2 resection.
Chemoradiation: principally for selected GEJ disease, positive margins, or inadequate nodal surgery rather than universally after optimal D2 surgery.

A 2024 guideline abstract summarizes the current standard directly: “Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors” with biomarker profiling in metastatic disease. (Publication: July 2024; https://doi.org/10.1007/s12094-024-03600-7.) (rivera2024seomgemcadttdclinicalguideline pages 1-2)

Unresectable/metastatic disease

A fluoropyrimidine–platinum doublet is the backbone. Add treatment according to biomarkers and jurisdiction:

HER2-positive: trastuzumab plus chemotherapy; pembrolizumab is added in eligible PD-L1-positive first-line disease. Trastuzumab deruxtecan is an important later-line antibody–drug conjugate after trastuzumab exposure.
HER2-negative, PD-L1-positive or MSI-H/dMMR: nivolumab or pembrolizumab plus chemotherapy; MSI-H tumors are particularly immunotherapy-sensitive.
CLDN18.2-positive, HER2-negative: zolbetuximab plus an oxaliplatin/fluoropyrimidine regimen. Zolbetuximab binds exposed CLDN18.2 and induces antibody- and complement-dependent cytotoxicity.
Second line: paclitaxel plus ramucirumab or alternatives; irinotecan/taxanes as appropriate.
Later line: trifluridine/tipiracil, trastuzumab deruxtecan for HER2 disease, checkpoint blockade in qualifying biomarker groups, or trial enrollment.

Current guidance therefore treats HER2, PD-L1 CPS, MSI/MMR, and CLDN18.2 as mandatory decision variables rather than merely prognostic assays. (lordick2024systemictherapyof pages 8-10, wang2024thechinesesociety pages 4-5)

Toxicities include cytopenias, neuropathy, mucositis/diarrhea, nausea, cardiotoxicity with HER2-directed agents, immune-related events with checkpoint blockade, hypertension/proteinuria/bleeding with antiangiogenic therapy, interstitial lung disease with trastuzumab deruxtecan, and prominent nausea/vomiting with zolbetuximab. No CPIC gastric-cancer-specific genotype-guided regimen is standard; DPYD and UGT1A1 testing may inform fluoropyrimidine or irinotecan safety according to regional pharmacogenomic practice.

Supportive, rehabilitative, and experimental treatment

Nutrition assessment, enteral support when feasible, B12 after total gastrectomy, iron/folate replacement, antiemetics, analgesia, management of obstruction/bleeding/ascites, exercise rehabilitation, and early palliative care are integral. Gene therapy and RNA therapy are not established. CLDN18.2 CAR-T is experimental; one 2024 report described a target-lesion complete response and an eight-month overall partial response after CT041 in a patient refractory to four lines, with ctDNA decline and no severe toxicity—important proof of concept, not population-level efficacy.

Representative recruiting or planned studies identified in ClinicalTrials.gov include perioperative FLOT versus adjuvant XELOX (NCT05264896), cadonilimab plus nab-paclitaxel after PD-(L)1 resistance (NCT06118645), sentinel-node magnetic mapping (NCT05038098), and a phase III CLDN18.2-directed antibody/PD-1/chemotherapy program (NCT07584135). Registry status and identifiers should be rechecked before reuse because trial records change.

13. Prevention

Primary prevention: detect and eradicate H. pylori; confirm cure; reduce tobacco and high-salt/preserved-food exposure; support healthy weight and diet. There is no licensed prophylactic H. pylori vaccine. Eradication is most effective before advanced precancerous lesions but also prevents ulcer disease, MALT lymphoma, iron deficiency, and B12 deficiency. (leja2024wherearewe pages 3-4)

Secondary prevention: Japan uses endoscopic screening from age 50; Korea offers endoscopy or upper-GI series every two years from age 40, although endoscopy is superior. Reported sensitivity and detection were 69.0% and 2.61/1,000 for endoscopy versus 36.7% and 0.68/1,000 for radiographic series. A Chinese program across 110 counties was associated with a 15% reduction in gastric-cancer mortality. (mok2024racialdisparitiesof pages 7-8, mok2024racialdisparitiesof pages 5-7)

Europe had no organized gastric-cancer screening program as of 2024; expert analysis judged population H. pylori “screen and treat” the most supportable strategy in intermediate/high-incidence regions while EUROHELICAN, TOGAS, GISTAR, and EUCanScreen generate implementation evidence. General-population endoscopy is not cost-effective in the United States, but risk-targeted screening may be reasonable for immigrants from high-incidence regions, high-risk racial/ethnic groups, premalignant gastric conditions, and first-degree family history. (leja2024wherearewe pages 6-6, leja2024wherearewe pages 6-7, mok2024racialdisparitiesof pages 8-9)

Hereditary prevention: offer genetic counseling, cascade testing, and management in expert centers. Risk-reducing total gastrectomy remains the most definitive intervention for appropriate pathogenic CDH1 carriers; expert endoscopic surveillance is an alternative for selected carriers who defer surgery, recognizing imperfect sensitivity. Female CDH1 carriers require lobular-breast-cancer surveillance. (sluis2024currentadvancesand pages 1-2, gullo2020precancerouslesionsof pages 15-17)

Tertiary prevention: postoperative surveillance, nutritional replacement, smoking cessation, rehabilitation, treatment of H. pylori, and prompt management of recurrence and treatment complications.

14. Other species and natural disease

Naturally occurring gastric adenocarcinoma occurs in dogs (NCBI Taxon 9615), cats (9685), and occasionally other mammals, but is uncommon relative to human disease. Certain dog breeds have reported predisposition, making canine gastric carcinoma a potential comparative-oncology resource; robust VBO mappings and universally accepted breed-specific penetrance estimates are not available from the evidence assembled here. Comparative pathology may reproduce glandular, diffuse/signet-ring, invasive, and metastatic features, while species differences in incidence, anatomy, microbiota, exposures, and driver spectra limit direct translation.

Orthologues of CDH1, CTNNA1, APC, TP53, ERBB2, ARID1A, and RHOA are conserved in mouse, dog, zebrafish, and other vertebrates. Gastric adenocarcinoma itself is neither zoonotic nor transmissible; Helicobacter species can cross host boundaries in selected settings, but human gastric cancer is not acquired from an animal tumor.

15. Model organisms and experimental systems

Cell lines/2D culture: scalable for signaling and drug screens, but lose architecture and clonal/TME complexity.
Patient-derived organoids: preserve epithelial genetics and three-dimensional organization and enable drug testing, CRISPR editing, and H. pylori microinjection. They incompletely retain immune, vascular, neural, microbial, and stromal components.
Genetically engineered organoids: CDH1 knockout models reproduce disrupted organization/spindle dynamics; Apc-deficient infected organoids demonstrate Wnt–H. pylori synergy.
Mouse models: chemical carcinogenesis, Helicobacter felis/pylori infection, conditional Cdh1, Apc, Trp53, Smad4 alteration, and transgenic oncogene systems investigate initiation and progression. No single mouse model reproduces human latency, histologic diversity, immune ecology, and metastasis.
Patient-derived xenografts: retain major tumor architecture/genomics and support drug testing but select for engrafting clones, replace human stroma over time, and usually require immunodeficient hosts.
Humanized mice, organ-on-chip, and co-culture: improve immune/microbial/biophysical modeling but remain costly and technically variable.
Zebrafish xenografts: rapid imaging and screening, with limitations in gastric anatomy and mammalian immunity.

A recent spatial study emphasizes the scale of heterogeneity: 64 tumor subregions showed expression differences between superficial tumor, deep tumor, and nodal metastasis. Consequently, models and clinical biopsies should be interpreted as samples of an evolving ecosystem rather than complete representations of the disease. (liang2024theburgeoningspatial pages 19-20, deng2023singlecelltranscriptomesequencing pages 4-5)

Evidence limitations and interpretation

The strongest evidence in this report comes from human guidelines, pathology series, randomized screening/treatment evidence summarized in those guidelines, and large molecular cohorts. Single-cell, spatial, organoid, CAR-T case, and animal findings are mechanistically informative but not yet routine standards. Biomarker frequencies vary by assay and population. HDGC penetrance is especially sensitive to family ascertainment; older high-risk-family estimates should not be combined naively with newer population-based estimates. Exact PMID values were not available for every retrieved 2023–2024 source, so DOI URLs and publication dates are supplied rather than inventing PMIDs. Core recent sources include the CSCO guideline (December 2024, https://doi.org/10.1002/cac2.12516), SEOM guideline (July 2024, https://doi.org/10.1007/s12094-024-03600-7), systemic-therapy review (September 2024, https://doi.org/10.3390/cancers16193337), European screening review (September 2024, https://doi.org/10.1136/gutjnl-2024-332705), and HDGC review (October 2024, https://doi.org/10.1186/s13053-024-00293-5). (lordick2024systemictherapyof pages 8-10, leja2024wherearewe pages 6-6, sluis2024currentadvancesand pages 1-2, wang2024thechinesesociety pages 4-5, rivera2024seomgemcadttdclinicalguideline pages 1-2)

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(gullo2020precancerouslesionsof pages 14-15): Irene Gullo, Federica Grillo, Luca Mastracci, Alessandro Vanoli, Fatima Carneiro, Luca Saragoni, Francesco Limarzi, Jacopo Ferro, Paola Parente, and Matteo Fassan. Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica, 112:166-185, Sep 2020. URL: https://doi.org/10.32074/1591-951x-166, doi:10.32074/1591-951x-166. This article has 233 citations.
(gullo2020precancerouslesionsof pages 15-17): Irene Gullo, Federica Grillo, Luca Mastracci, Alessandro Vanoli, Fatima Carneiro, Luca Saragoni, Francesco Limarzi, Jacopo Ferro, Paola Parente, and Matteo Fassan. Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica, 112:166-185, Sep 2020. URL: https://doi.org/10.32074/1591-951x-166, doi:10.32074/1591-951x-166. This article has 233 citations.
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Gastric Adenocarcinoma: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

2. Etiology, risks, protection, and gene–environment interaction

Causal and environmental factors

Genetic susceptibility

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Gene–environment interaction

3. Phenotypes and quality-of-life effects

4. Genetic and molecular information

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9. Inheritance and population epidemiology

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Evidence limitations and interpretation

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