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.

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

1. 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.
2. 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)
3. EBV pathway: latent viral infection → epigenetic reprogramming and immune-checkpoint-rich microenvironment → EBV+ adenocarcinoma.
4. 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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