CDH1-Related Hereditary Diffuse Gastric Cancer

Mendelian MONDO:0100488 Pathograph 7 Show in embeddings browser hereditary cancer-predisposing syndrome

CDH1-related hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome caused by inactivating germline variants in CDH1, encoding the calcium-dependent cell-adhesion protein E-cadherin. Carriers are at high risk of diffuse (signet-ring cell, poorly cohesive) gastric carcinoma and, in women, of lobular breast carcinoma; a minority of HDGC families instead carry pathogenic CTNNA1 variants, which are out of scope for this entry. The mechanism is distinctive among the hereditary cancer syndromes in that the tumor suppressor lost is an adhesion molecule rather than a growth-control or genome-maintenance protein. Loss of E-cadherin removes the adherens-junction tether between epithelial cells, which is why the resulting carcinoma is diffusely infiltrative rather than mass-forming — the signet-ring cells spread singly through the gastric wall beneath an intact mucosal surface. That histological behaviour is the reason the syndrome is managed differently from every other gastrointestinal cancer predisposition: because early lesions form no endoscopically visible mass and are missed by random biopsy, prophylactic total gastrectomy — not surveillance — remains the recommended risk-management option for pathogenic CDH1 variant carriers, with endoscopic surveillance in expert centres reserved for those who wish to postpone surgery or whose risk is not well defined.

Ask OpenScientist

Ask a research question about CDH1-Related Hereditary Diffuse Gastric Cancer. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
4
Pathophys.
3
Phenotypes
7
Pathograph
1
Genes
3
Medical Actions
1
Trials
1
References
👪

Inheritance

1
Autosomal dominant HP:0000006
HDGC segregates as an autosomal dominant cancer predisposition. Gastric cancer risk is not uniform across carriers: the updated international guidelines explicitly recognise variability in gastric cancer risk between HDGC families, which is what justifies offering surveillance rather than immediate gastrectomy to some carriers.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (3 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."
States the inheritance pattern and the two cardinal tumor types.
PMID:20301318 SUPPORT Other
"Each child of an individual with DGLBCS has a 50% chance of inheriting the DGLBCS-related pathogenic variant."
GeneReviews Genetic Counseling section: the transmission risk to offspring. Evidence source is OTHER because GeneReviews is an expert-authored review rather than a primary study.
PMID:20301318 SUPPORT Other
"The majority of individuals diagnosed with CDH1-related DGLBCS inherited the CDH1 pathogenic variant from a parent (because of reduced penetrance, the parent from whom the pathogenic variant was inherited may not have developed cancer)."
GeneReviews Genetic Counseling section, supporting the reduced penetrance recorded on this inheritance block: an unaffected transmitting parent is expected rather than evidence against the diagnosis.
⚙

Pathophysiology

4
Germline CDH1 First-Hit Inactivation
A heterozygous inactivating variant in CDH1 is present constitutionally. The founding New Zealand kindred carried a donor splice-site substitution in exon 7 producing a truncated protein, and inactivating frameshift and nonsense alleles were then found in further gastric cancer families. One functional E-cadherin allele is sufficient for normal epithelial adhesion, so the constitutional state is a susceptibility rather than a disease.
CDH1 hgnc:1748 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves decreased CDH1 (hgnc:1748). hgnc:1748 is a gene from the HUGO Gene Nomenclature Committee. ↓ DECREASED
Genetic context CDH1 hgnc:1748 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CDH1 (hgnc:1748). hgnc:1748 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE allelic_hit_role: FIRST_HIT allelic_event: PATHOGENIC_VARIANT allelic_event: SPLICE_SITE_VARIANT zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Constitutional heterozygous inactivating CDH1 variant; splice-site, frameshift and nonsense alleles were all identified in the original gastric cancer families.
Downstream
Biallelic E-Cadherin Loss in Gastric Epithelium A somatic event removing the retained wild-type allele is required before an epithelial cell loses adhesion function.
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."
Identifies the founding germline CDH1 lesion in the kindred that defined the syndrome.
PMID:9537325 SUPPORT Human Clinical
"The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families."
Confirms that the germline lesion generalizes beyond the index family, which is what establishes CDH1 as the susceptibility gene.
Biallelic E-Cadherin Loss in Gastric Epithelium
In a gastric epithelial cell that has inactivated the retained CDH1 allele, E-cadherin is absent and the adherens junction cannot be assembled. The route to that second hit is distinctive and diagnostically important: HDGC cancers consistently show ABSENCE of loss of heterozygosity at the CDH1 locus, and the second hit is instead epigenetic — promoter hypermethylation silencing the wild-type allele. A carrier's tumor with no detectable LOH has therefore not escaped the two-hit mechanism; it has completed it by the epigenetic route the germline_two_hit_tumor_predisposition module lists alongside deletion and intragenic mutation. Diminished E-cadherin expression is a general correlate of aggressive, poorly differentiated carcinoma across tumor types, and restoring it in tumor models suppresses the invasiveness of epithelial tumor cells — so the adhesion protein is not merely a marker of the phenotype but part of what restrains it.
cell-cell adhesion GO:0098609 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cell-cell adhesion (GO:0098609), qualified as loss of function. GO:0098609 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Diffusely Infiltrative Signet-Ring Cell Carcinoma Without the adherens-junction tether, transformed cells infiltrate singly through the gastric wall instead of forming a cohesive mass.
Show evidence (4 references)
PMID:10973239 SUPPORT Human Clinical
"These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus."
Establishes that the second hit in HDGC is not loss of heterozygosity, which is the observation that sends the mechanism to the epigenetic route and is why this entry does not curate LOH.
PMID:10973239 SUPPORT Human Clinical
"These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers."
Names promoter hypermethylation as the second hit in HDGC, which is the biallelic-inactivation claim this node makes. The source states it as the hypothesis its data test, and that hedging is preserved here.
PMID:9537325 SUPPORT Human Clinical
"Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas."
Links loss of the protein to the poorly differentiated phenotype that characterizes diffuse gastric carcinoma.
+ 1 more reference
Diffusely Infiltrative Signet-Ring Cell Carcinoma
Clonal expansion of E-cadherin-null cells produces the characteristic lesion: poorly cohesive signet-ring cells spreading diffusely beneath an intact mucosal surface rather than a discrete tumor. The clinical consequence is that early disease is endoscopically occult, which is what forces the syndrome's management toward prophylactic surgery rather than surveillance.
Downstream
Diffuse Gastric and Lobular Breast Cancer Risk Repeated independent initiation events across gastric epithelium, and the equivalent process in breast lobular epithelium, produce the syndrome's lifetime cancer risk.
Show evidence (1 reference)
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)."
Characterizes the tumor as early-onset, poorly differentiated and diffuse — the histological phenotype this node asserts.
Diffuse Gastric and Lobular Breast Cancer Risk
The clinical output: a high prevalence of diffuse gastric cancer, typically at an age well below that of sporadic gastric cancer, and lobular breast cancer in female carriers — notably the lobular subtype specifically, which is itself characterized by E-cadherin loss. Gastrectomy specimens from asymptomatic carriers characteristically contain multiple independent microscopic foci, the direct histological signature of repeated independent second hits across the organ.
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 CDH1 as the predominant cause of the syndrome's cancer risk and delimits the CTNNA1 minority that this entry excludes.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CDH1-Related Hereditary Diffuse Gastric Cancer Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

3
Breast 1
Lobular Breast Carcinoma HP:0003002 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Breast carcinoma (HP:0003002). HP:0003002 is a phenotype from the Human Phenotype Ontology.
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."
Names lobular breast cancer as the second cardinal tumor of the syndrome.
PMID:20301318 SUPPORT Other
"In females with CDH1-related DGLBCS, but not in males, there is also an increased risk for lobular breast cancer (LBC), characterized by small, non-cohesive cells dispersed in the stroma or arranged in single-file infiltrating patterns."
GeneReviews Clinical Characteristics section. Note the sex restriction it states — the lobular breast cancer risk applies to females and not males — and the non-cohesive histology, which is the same adhesion defect expressed in a second organ.
Digestive 1
Diffuse Gastric Carcinoma Stomach cancer HP:0012126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stomach cancer (HP:0012126). HP:0012126 is a phenotype from the Human Phenotype Ontology.
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."
Names diffuse gastric cancer as the defining tumor of the syndrome.
PMID:20301318 SUPPORT Other
"a poorly differentiated adenocarcinoma (also referred to as signet ring cell carcinoma or isolated cell-type carcinoma) that infiltrates into the stomach wall, causing thickening of the wall (linitis plastica) without forming a distinct mass"
GeneReviews Clinical Characteristics section, describing diffusely infiltrative growth without a distinct mass — the histological behaviour that makes early disease endoscopically occult and drives this syndrome's surgical management.
Head and Neck 1
Cleft Lip HP:0410030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip (HP:0410030). HP:0410030 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301318 SUPPORT Other
"Cleft lip with or without cleft palate has also been reported in some individuals with CDH1-related DGLBCS."
GeneReviews Clinical Characteristics section. The hedged wording ("some individuals") is preserved: this is a reported association, not a penetrant feature.
🧬

Genetic Associations

1
CDH1
Gene: CDH1 hgnc:1748 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CDH1 (hgnc:1748). hgnc:1748 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
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 CDH1 as the causative gene and identifies CTNNA1 as the alternative locus in a minority of families.
💊

Medical Actions

3
Prophylactic Total Gastrectomy
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Removal of the entire at-risk gastric epithelium before a second hit can produce invasive disease. This is the recommended gastric-cancer risk management option for pathogenic CDH1 variant carriers, and it is the clearest example in this KB of an intervention whose rationale is read directly off the two-hit mechanism: because every gastric epithelial cell carries the first hit and early lesions are endoscopically occult, removing the organ is more reliable than detecting the lesion.
Mechanism Target:
INHIBITS Diffuse Gastric and Lobular Breast Cancer Risk — Gastrectomy does not alter the germline lesion; it removes the tissue in which second hits would otherwise produce gastric cancer, acting on the consequence node.
Show evidence (2 references)
PMID:32758476 SUPPORT Human Clinical
"Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers."
Direct guideline recommendation for the intervention curated here.
PMID:20301318 SUPPORT Other
"Prophylactic gastrectomy for diffuse gastric cancer is an option from early adulthood in individuals with normal endoscopy / gastric biopsies and a DGLBCS-related CDH1 pathogenic variant regardless of family history"
GeneReviews Management section. Note the two conditions it attaches: normal endoscopy and biopsies beforehand, and independence from family history — the second follows directly from the two-hit mechanism, since every gastric cell already carries the first hit whether or not a relative has yet had cancer.
Endoscopic Surveillance in Expert Centres
Action: Therapeutic ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. NCIT:C49236
The alternative for carriers who wish to postpone gastrectomy, or whose gastric cancer risk is not well defined. The guideline's confidence in this option has increased but it is explicitly conditioned on expert-centre delivery, reflecting the difficulty of detecting an endoscopically occult lesion.
Show evidence (2 references)
PMID:32758476 SUPPORT Human Clinical
"However, 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."
The guideline's own conditional endorsement of surveillance, including the conditions attached to it.
PMID:20301318 SUPPORT Other
"referral to a high-risk gastric screening program with a thorough ≥30-minute upper endoscopy with multiple targeted and random biopsies every six to 12 months beginning in early adulthood"
GeneReviews Management section, giving the concrete surveillance protocol — duration, biopsy strategy, interval and starting age. The random-biopsy requirement exists precisely because the lesion forms no visible mass.
High-Risk Breast Cancer Surveillance
Action: Magnetic Resonance ImagingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Magnetic Resonance Imaging (NCIT:C16809). NCIT:C16809 is a clinical intervention from the NCI Thesaurus. NCIT:C16809
Because female carriers are additionally at risk of lobular breast cancer, breast surveillance runs in parallel with gastric management: clinical examination and contrast breast MRI from age 30, with mammography between MRI screens. Risk-reducing contralateral mastectomy is a consideration after a breast cancer diagnosis rather than a primary preventive step.
Mechanism Target:
INHIBITS Diffuse Gastric and Lobular Breast Cancer Risk — Surveillance does not alter the germline lesion; it shifts detection of the breast arm of the tumor spectrum earlier, acting on the consequence node.
Show evidence (2 references)
PMID:20301318 SUPPORT Other
"annual clinical breast examinations, education on clinical features of breast cancer, and bilateral breast MRI with contrast from age 30 years; annual mammography between MRI screens from age 30-40 years"
GeneReviews Management section, giving the breast surveillance protocol and its starting age for female carriers.
PMID:20301318 SUPPORT Other
"surgery, hormonal therapy, and perioperative and/or adjuvant chemotherapy for LBC; consider risk-reducing contralateral mastectomy"
GeneReviews Management section, giving the treatment of established lobular breast cancer and, after it, the contralateral risk-reducing option. Quoted as the hedged consideration it is ("consider") and with the preceding clause included, which places it as a post-diagnosis decision rather than a primary preventive recommendation.
🔬

Diagnosis

2
Molecular Genetic Testing for CDH1
The diagnosis rests on identifying a germline heterozygous pathogenic variant in CDH1 (or a truncating CTNNA1 variant, which is outside this entry's scope) in an individual with suggestive findings. A family meeting consensus testing criteria without an identified variant is classified as suspected disease of unknown genetic cause rather than excluded — an important distinction, because those families still receive gastric surveillance.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A germline heterozygous pathogenic CDH1 variant establishes the diagnosis and makes at-risk relatives eligible for predictive testing.
Show evidence (2 references)
PMID:20301318 SUPPORT Other
"The diagnosis of DGLBCS can be established in an individual with suggestive findings and a germline heterozygous pathogenic variant in CDH1 or a germline heterozygous truncating pathogenic variant in CTNNA1 identified by molecular genetic testing."
GeneReviews Diagnosis/Testing section, stating the confirmatory test and the variant classes that establish the diagnosis.
PMID:20301318 SUPPORT Other
"Affected individuals from families that meet consensus genetic testing criteria for DGLBCS who do not have an identified pathogenic variant in CDH1 or CTNNA1 have suspected DGLBCS of unknown genetic cause (also referred to as hereditary diffuse gastric cancer [HDGC]-like)."
GeneReviews Diagnosis/Testing section, defining the variant-negative category — the reason a negative test does not discharge a family from surveillance.
Upper Endoscopy with Targeted and Random Biopsies
Endoscopic assessment with multiple targeted and random biopsies is both the surveillance modality and the precondition for offering prophylactic gastrectomy. Because early lesions form no distinct mass, random sampling rather than targeted biopsy of a visible lesion is what carries the diagnostic yield.
Esophagogastroduodenoscopy NCIT:C78144 NCI Thesaurus (NCIT)
Results: Normal endoscopy and gastric biopsies are the stated precondition for offering prophylactic total gastrectomy to a CDH1 variant carrier.
Show evidence (1 reference)
PMID:20301318 SUPPORT Other
"Prophylactic gastrectomy for diffuse gastric cancer is an option from early adulthood in individuals with normal endoscopy / gastric biopsies and a DGLBCS-related CDH1 pathogenic variant regardless of family history"
GeneReviews Management section, which makes normal endoscopy and biopsies the precondition for the prophylactic operation — the diagnostic role this entry curates.
🔬

Clinical Trials

1
NCT04253106 NOT_APPLICABLE COMPLETED
Completed pilot study of blood and gastric-fluid liquid biopsy in CDH1 and CTNNA1 carriers, aimed at the central clinical problem in HDGC: signet-ring foci that endoscopy cannot see.
Target Phenotypes: Diffuse gastric cancer HP:0012126 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Diffuse gastric cancer, annotated with Stomach cancer (HP:0012126). HP:0012126 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04253106 SUPPORT Human Clinical
"Activating somatic mutations and methylation profiles identified by liquid biopsies could identify CDH1 and CTNNA1 pathogenic variants carriers with invasive diffuse gastric cancer undetectable by upper G-I endoscopy."
Registry record stating the trial hypothesis, which rests on the endoscopic occultness of early diffuse gastric cancer in CDH1 carriers.
{ }

Source YAML

click to show 
name: CDH1-Related Hereditary Diffuse Gastric Cancer
creation_date: "2026-08-23T00:00:00Z"
category: Mendelian
categories:
- Hereditary Cancer Syndrome
- Cancer Predisposition Syndrome
- Gastrointestinal Neoplasia
parents:
- hereditary cancer-predisposing syndrome
disease_term:
  preferred_term: CDH1-related diffuse gastric and lobular breast cancer syndrome
  term:
    id: MONDO:0100488
    label: CDH1-related diffuse gastric and lobular breast cancer syndrome
synonyms:
- HDGC
- hereditary diffuse gastric cancer
- E-cadherin-related gastric cancer syndrome
description: >-
  CDH1-related hereditary diffuse gastric cancer (HDGC) is an autosomal dominant
  cancer syndrome caused by inactivating germline variants in CDH1, encoding the
  calcium-dependent cell-adhesion protein E-cadherin. Carriers are at high risk
  of diffuse (signet-ring cell, poorly cohesive) gastric carcinoma and, in women,
  of lobular breast carcinoma; a minority of HDGC families instead carry
  pathogenic CTNNA1 variants, which are out of scope for this entry. The
  mechanism is distinctive among the hereditary cancer syndromes in that the
  tumor suppressor lost is an adhesion molecule rather than a growth-control or
  genome-maintenance protein. Loss of E-cadherin removes the adherens-junction
  tether between epithelial cells, which is why the resulting carcinoma is
  diffusely infiltrative rather than mass-forming — the signet-ring cells spread
  singly through the gastric wall beneath an intact mucosal surface. That
  histological behaviour is the reason the syndrome is managed differently from
  every other gastrointestinal cancer predisposition: because early lesions form
  no endoscopically visible mass and are missed by random biopsy, prophylactic
  total gastrectomy — not surveillance — remains the recommended risk-management
  option for pathogenic CDH1 variant carriers, with endoscopic surveillance in
  expert centres reserved for those who wish to postpone surgery or whose risk is
  not well defined.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    HDGC segregates as an autosomal dominant cancer predisposition. Gastric
    cancer risk is not uniform across carriers: the updated international
    guidelines explicitly recognise variability in gastric cancer risk between
    HDGC families, which is what justifies offering surveillance rather than
    immediate gastrectomy to some carriers.
  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: >-
      States the inheritance pattern and the two cardinal tumor types.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with DGLBCS has a 50% chance of inheriting the
      DGLBCS-related pathogenic variant.
    explanation: >-
      GeneReviews Genetic Counseling section: the transmission risk to
      offspring. Evidence source is OTHER because GeneReviews is an
      expert-authored review rather than a primary study.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The majority of individuals diagnosed with CDH1-related DGLBCS inherited
      the CDH1 pathogenic variant from a parent (because of reduced penetrance,
      the parent from whom the pathogenic variant was inherited may not have
      developed cancer).
    explanation: >-
      GeneReviews Genetic Counseling section, supporting the reduced penetrance
      recorded on this inheritance block: an unaffected transmitting parent is
      expected rather than evidence against the diagnosis.
pathophysiology:
- name: Germline CDH1 First-Hit Inactivation
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  description: >-
    A heterozygous inactivating variant in CDH1 is present constitutionally.
    The founding New Zealand kindred carried a donor splice-site substitution in
    exon 7 producing a truncated protein, and inactivating frameshift and
    nonsense alleles were then found in further gastric cancer families. One
    functional E-cadherin allele is sufficient for normal epithelial adhesion, so
    the constitutional state is a susceptibility rather than a disease.
  role: trigger
  biological_scale: MOLECULAR
  gene:
    preferred_term: CDH1
    modifier: DECREASED
    term:
      id: hgnc:1748
      label: CDH1
  genetic_context:
    gene:
      preferred_term: CDH1
      term:
        id: hgnc:1748
        label: CDH1
    variant_origin: GERMLINE
    allelic_hit_role: FIRST_HIT
    allelic_events:
    - PATHOGENIC_VARIANT
    - SPLICE_SITE_VARIANT
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Constitutional heterozygous inactivating CDH1 variant; splice-site,
      frameshift and nonsense alleles were all identified in the original
      gastric cancer families.
  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: >-
      Identifies the founding germline CDH1 lesion in the kindred that defined
      the syndrome.
  - reference: PMID:9537325
    reference_title: E-cadherin germline mutations in familial gastric cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The role of E-cadherin in gastric cancer susceptibility was confirmed by
      identifying inactivating mutations in other gastric cancer families.
    explanation: >-
      Confirms that the germline lesion generalizes beyond the index family,
      which is what establishes CDH1 as the susceptibility gene.
  downstream:
  - target: Biallelic E-Cadherin Loss in Gastric Epithelium
    description: >-
      A somatic event removing the retained wild-type allele is required before
      an epithelial cell loses adhesion function.

- name: Biallelic E-Cadherin Loss in Gastric Epithelium
  conforms_to: "germline_two_hit_tumor_predisposition#Biallelic Tumor Suppressor Inactivation in a Susceptible Cell"
  description: >-
    In a gastric epithelial cell that has inactivated the retained CDH1 allele,
    E-cadherin is absent and the adherens junction cannot be assembled. The
    route to that second hit is distinctive and diagnostically important: HDGC
    cancers consistently show ABSENCE of loss of heterozygosity at the CDH1
    locus, and the second hit is instead epigenetic — promoter hypermethylation
    silencing the wild-type allele. A carrier's tumor with no detectable LOH has
    therefore not escaped the two-hit mechanism; it has completed it by the
    epigenetic route the germline_two_hit_tumor_predisposition module lists
    alongside deletion and intragenic mutation.
    Diminished E-cadherin expression is a general correlate of aggressive, poorly
    differentiated carcinoma across tumor types, and restoring it in tumor models
    suppresses the invasiveness of epithelial tumor cells — so the adhesion
    protein is not merely a marker of the phenotype but part of what restrains
    it.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cell-cell adhesion
    term:
      id: GO:0098609
      label: cell-cell adhesion
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:10973239
    reference_title: Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals harbour germline mutations in the gene encoding
      E-cadherin, CDH1, but their cancers have consistently demonstrated absence
      of loss of heterozygosity at the CDH1 locus.
    explanation: >-
      Establishes that the second hit in HDGC is not loss of heterozygosity,
      which is the observation that sends the mechanism to the epigenetic route
      and is why this entry does not curate LOH.
  - reference: PMID:10973239
    reference_title: Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggested the hypothesis that CDH1 promoter methylation
      might function as the 'second genetic hit' in the genesis of these
      cancers.
    explanation: >-
      Names promoter hypermethylation as the second hit in HDGC, which is the
      biallelic-inactivation claim this node makes. The source states it as the
      hypothesis its data test, and that hedging is preserved here.
  - 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: >-
      Links loss of the protein to the poorly differentiated phenotype that
      characterizes diffuse gastric carcinoma.
  - reference: PMID:9537325
    reference_title: E-cadherin germline mutations in familial gastric cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      restored expression of E-cadherin in tumour models can suppress the
      invasiveness of epithelial tumour cells
    explanation: >-
      Rescue evidence that E-cadherin loss is causal for the invasive phenotype
      rather than a correlate. Evidence source is IN_VITRO (tumor model systems).
  downstream:
  - target: Diffusely Infiltrative Signet-Ring Cell Carcinoma
    description: >-
      Without the adherens-junction tether, transformed cells infiltrate singly
      through the gastric wall instead of forming a cohesive mass.

- name: Diffusely Infiltrative Signet-Ring Cell Carcinoma
  conforms_to: "germline_two_hit_tumor_predisposition#Clonal Expansion and Tumor Initiation"
  description: >-
    Clonal expansion of E-cadherin-null cells produces the characteristic
    lesion: poorly cohesive signet-ring cells spreading diffusely beneath an
    intact mucosal surface rather than a discrete tumor. The clinical
    consequence is that early disease is endoscopically occult, which is what
    forces the syndrome's management toward prophylactic surgery rather than
    surveillance.
  role: effector
  biological_scale: TISSUE
  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: >-
      Characterizes the tumor as early-onset, poorly differentiated and diffuse
      — the histological phenotype this node asserts.
  downstream:
  - target: Diffuse Gastric and Lobular Breast Cancer Risk
    description: >-
      Repeated independent initiation events across gastric epithelium, and the
      equivalent process in breast lobular epithelium, produce the syndrome's
      lifetime cancer risk.

- name: Diffuse Gastric and Lobular Breast Cancer Risk
  conforms_to: "germline_two_hit_tumor_predisposition#Early-Onset, Multifocal, and Bilateral Tumor Spectrum"
  description: >-
    The clinical output: a high prevalence of diffuse gastric cancer, typically
    at an age well below that of sporadic gastric cancer, and lobular breast
    cancer in female carriers — notably the lobular subtype specifically, which
    is itself characterized by E-cadherin loss. Gastrectomy specimens from
    asymptomatic carriers characteristically contain multiple independent
    microscopic foci, the direct histological signature of repeated independent
    second hits across the organ.
  role: consequence
  biological_scale: ORGANISM
  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 CDH1 as the predominant cause of the syndrome's cancer risk
      and delimits the CTNNA1 minority that this entry excludes.
phenotypes:
- category: Gastrointestinal
  name: Diffuse Gastric Carcinoma
  description: >-
    Poorly cohesive, signet-ring cell gastric adenocarcinoma of early onset,
    infiltrating diffusely and often endoscopically occult at an early stage.
  phenotype_term:
    preferred_term: Stomach cancer
    term:
      id: HP:0012126
      label: Stomach cancer
  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: >-
      Names diffuse gastric cancer as the defining tumor of the syndrome.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a poorly differentiated adenocarcinoma (also referred to as signet ring
      cell carcinoma or isolated cell-type carcinoma) that infiltrates into the
      stomach wall, causing thickening of the wall (linitis plastica) without
      forming a distinct mass
    explanation: >-
      GeneReviews Clinical Characteristics section, describing diffusely
      infiltrative growth without a distinct mass — the histological behaviour
      that makes early disease endoscopically occult and drives this syndrome's
      surgical management.
- category: Neoplastic
  name: Lobular Breast Carcinoma
  description: >-
    Invasive lobular carcinoma of the breast in female carriers — the subtype
    whose sporadic form is also characterized by E-cadherin loss.
  phenotype_term:
    preferred_term: 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: >-
      Names lobular breast cancer as the second cardinal tumor of the syndrome.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In females with CDH1-related DGLBCS, but not in males, there is also an
      increased risk for lobular breast cancer (LBC), characterized by small,
      non-cohesive cells dispersed in the stroma or arranged in single-file
      infiltrating patterns.
    explanation: >-
      GeneReviews Clinical Characteristics section. Note the sex restriction it
      states — the lobular breast cancer risk applies to females and not males —
      and the non-cohesive histology, which is the same adhesion defect
      expressed in a second organ.
- category: Craniofacial
  name: Cleft Lip
  description: >-
    Cleft lip with or without cleft palate is reported in some individuals with
    CDH1-related disease, reflecting E-cadherin's developmental role in
    epithelial fusion. It is not a neoplastic feature and is not present in most
    carriers, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
  evidence:
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cleft lip with or without cleft palate has also been reported in some
      individuals with CDH1-related DGLBCS.
    explanation: >-
      GeneReviews Clinical Characteristics section. The hedged wording ("some
      individuals") is preserved: this is a reported association, not a
      penetrant feature.
genetic:
- name: CDH1
  gene_term:
    preferred_term: CDH1
    term:
      id: hgnc:1748
      label: CDH1
  relationship_type: CAUSATIVE
  notes: >-
    CDH1 encodes E-cadherin. Inactivating germline variants are the predominant
    cause of hereditary diffuse gastric cancer; tumors additionally inactivate
    the retained allele.
  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 CDH1 as the causative gene and identifies CTNNA1 as the
      alternative locus in a minority of families.
treatments:
- name: Prophylactic Total Gastrectomy
  description: >-
    Removal of the entire at-risk gastric epithelium before a second hit can
    produce invasive disease. This is the recommended gastric-cancer risk
    management option for pathogenic CDH1 variant carriers, and it is the
    clearest example in this KB of an intervention whose rationale is read
    directly off the two-hit mechanism: because every gastric epithelial cell
    carries the first hit and early lesions are endoscopically occult, removing
    the organ is more reliable than detecting the lesion.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Diffuse Gastric and Lobular Breast Cancer Risk
    treatment_effect: INHIBITS
    description: >-
      Gastrectomy does not alter the germline lesion; it removes the tissue in
      which second hits would otherwise produce gastric cancer, acting on the
      consequence node.
  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: >-
      Direct guideline recommendation for the intervention curated here.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Prophylactic gastrectomy for diffuse gastric cancer is an option from
      early adulthood in individuals with normal endoscopy / gastric biopsies
      and a DGLBCS-related CDH1 pathogenic variant regardless of family history
    explanation: >-
      GeneReviews Management section. Note the two conditions it attaches:
      normal endoscopy and biopsies beforehand, and independence from family
      history — the second follows directly from the two-hit mechanism, since
      every gastric cell already carries the first hit whether or not a relative
      has yet had cancer.
- name: Endoscopic Surveillance in Expert Centres
  notes: >-
    Curated under `treatments:` as a management intervention, not as a claim
    that imaging or biochemistry is itself therapeutic. In a two-hit
    predisposition syndrome the second hit cannot be prevented, so the only
    available lever is stage at detection: surveillance is the intervention
    that converts an unavoidable tumor into a resectable one. Where a
    `target_mechanisms` link is present it points at the clinical-outcome node
    for that reason, and never at an upstream mechanistic node.
  description: >-
    The alternative for carriers who wish to postpone gastrectomy, or whose
    gastric cancer risk is not well defined. The guideline's confidence in this
    option has increased but it is explicitly conditioned on expert-centre
    delivery, reflecting the difficulty of detecting an endoscopically occult
    lesion.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:32758476
    reference_title: "Hereditary diffuse gastric cancer: updated clinical practice guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, 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: >-
      The guideline's own conditional endorsement of surveillance, including the
      conditions attached to it.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      referral to a high-risk gastric screening program with a thorough
      ≥30-minute upper endoscopy with multiple targeted and random biopsies
      every six to 12 months beginning in early adulthood
    explanation: >-
      GeneReviews Management section, giving the concrete surveillance protocol
      — duration, biopsy strategy, interval and starting age. The random-biopsy
      requirement exists precisely because the lesion forms no visible mass.
- name: High-Risk Breast Cancer Surveillance
  description: >-
    Because female carriers are additionally at risk of lobular breast cancer,
    breast surveillance runs in parallel with gastric management: clinical
    examination and contrast breast MRI from age 30, with mammography between
    MRI screens. Risk-reducing contralateral mastectomy is a consideration after
    a breast cancer diagnosis rather than a primary preventive step.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  target_mechanisms:
  - target: Diffuse Gastric and Lobular Breast Cancer Risk
    treatment_effect: INHIBITS
    description: >-
      Surveillance does not alter the germline lesion; it shifts detection of
      the breast arm of the tumor spectrum earlier, acting on the consequence
      node.
  evidence:
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      annual clinical breast examinations, education on clinical features of
      breast cancer, and bilateral breast MRI with contrast from age 30 years;
      annual mammography between MRI screens from age 30-40 years
    explanation: >-
      GeneReviews Management section, giving the breast surveillance protocol
      and its starting age for female carriers.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      surgery, hormonal therapy, and perioperative and/or adjuvant chemotherapy
      for LBC; consider risk-reducing contralateral mastectomy
    explanation: >-
      GeneReviews Management section, giving the treatment of established
      lobular breast cancer and, after it, the contralateral risk-reducing
      option. Quoted as the hedged consideration it is ("consider") and with the
      preceding clause included, which places it as a post-diagnosis decision
      rather than a primary preventive recommendation.
diagnosis:
- name: Molecular Genetic Testing for CDH1
  description: >-
    The diagnosis rests on identifying a germline heterozygous pathogenic
    variant in CDH1 (or a truncating CTNNA1 variant, which is outside this
    entry's scope) in an individual with suggestive findings. A family meeting
    consensus testing criteria without an identified variant is classified as
    suspected disease of unknown genetic cause rather than excluded — an
    important distinction, because those families still receive gastric
    surveillance.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A germline heterozygous pathogenic CDH1 variant establishes the diagnosis
    and makes at-risk relatives eligible for predictive testing.
  evidence:
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of DGLBCS can be established in an individual with
      suggestive findings and a germline heterozygous pathogenic variant in CDH1
      or a germline heterozygous truncating pathogenic variant in CTNNA1
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews Diagnosis/Testing section, stating the confirmatory test and
      the variant classes that establish the diagnosis.
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected individuals from families that meet consensus genetic testing
      criteria for DGLBCS who do not have an identified pathogenic variant in
      CDH1 or CTNNA1 have suspected DGLBCS of unknown genetic cause (also
      referred to as hereditary diffuse gastric cancer [HDGC]-like).
    explanation: >-
      GeneReviews Diagnosis/Testing section, defining the variant-negative
      category — the reason a negative test does not discharge a family from
      surveillance.
- name: Upper Endoscopy with Targeted and Random Biopsies
  description: >-
    Endoscopic assessment with multiple targeted and random biopsies is both the
    surveillance modality and the precondition for offering prophylactic
    gastrectomy. Because early lesions form no distinct mass, random sampling
    rather than targeted biopsy of a visible lesion is what carries the
    diagnostic yield.
  diagnosis_term:
    preferred_term: Esophagogastroduodenoscopy
    term:
      id: NCIT:C78144
      label: Esophagogastroduodenoscopy
  results: >-
    Normal endoscopy and gastric biopsies are the stated precondition for
    offering prophylactic total gastrectomy to a CDH1 variant carrier.
  evidence:
  - reference: PMID:20301318
    reference_title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Prophylactic gastrectomy for diffuse gastric cancer is an option from
      early adulthood in individuals with normal endoscopy / gastric biopsies
      and a DGLBCS-related CDH1 pathogenic variant regardless of family history
    explanation: >-
      GeneReviews Management section, which makes normal endoscopy and biopsies
      the precondition for the prophylactic operation — the diagnostic role this
      entry curates.
references:
- reference: PMID:20301318
  title: "Diffuse Gastric and Lobular Breast Cancer Syndrome."
  tags:
  - GeneReviews
clinical_trials:
- name: NCT04253106
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Completed pilot study of blood and gastric-fluid liquid biopsy in CDH1 and
    CTNNA1 carriers, aimed at the central clinical problem in HDGC: signet-ring
    foci that endoscopy cannot see.
  target_phenotypes:
  - preferred_term: Diffuse gastric cancer
    term:
      id: HP:0012126
      label: Stomach cancer
  evidence:
  - reference: clinicaltrials:NCT04253106
    reference_title: "Liquid Biopsies (blood, Gastric Fluid) for the Personalized Management of Patients with Hereditary Diffuse Gastric Cancer: a Pilot Project"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activating somatic mutations and methylation profiles identified by liquid biopsies could identify CDH1 and CTNNA1 pathogenic variants carriers with invasive diffuse gastric cancer undetectable by upper G-I endoscopy.
    explanation: >-
      Registry record stating the trial hypothesis, which rests on the
      endoscopic occultness of early diffuse gastric cancer in CDH1 carriers.
📚

References & Deep Research

References

1
PMID:20301318
Diffuse Gastric and Lobular Breast Cancer Syndrome.
No top-level findings curated for this source.