CDH1 – Hereditary Diffuse Gastric Adenocarcinoma

Hereditary diffuse gastric adenocarcinoma (HDGC) is an autosomal dominant cancer predisposition syndrome characterized by an elevated risk of diffuse-type gastric carcinoma and lobular breast carcinoma. Germline CDH1 mutations were first implicated in HDGC families in the late 1990s, with subsequent studies establishing the gene’s critical role in epithelial integrity (PMID:12647996). CDH1 encodes the calcium-dependent cell adhesion protein E-cadherin, which maintains gastric epithelial cohesion. Loss-of-function variants disrupt epithelial barriers and favor malignant transformation. Clinical guidelines now recommend CDH1 genetic testing for individuals from affected families to guide prophylactic gastrectomy and surveillance. The robust association between CDH1 mutations and HDGC informs diagnostic decision-making and targeted prevention strategies.

Autosomal dominant inheritance of HDGC is supported by multiple independent cohorts demonstrating germline CDH1 variants in affected individuals. A screen of 66 early-onset gastric cancer probands identified two novel missense mutations (c.1900G>T (p.Ala634Ser), c.1901C>T (p.Ala634Val)) and one intronic variant among apparently sporadic cases, with functional impairment confirmed by in vitro assays (PMID:12588804). Segregation analysis in Japanese HDGC families revealed the c.2494G>A (p.Val832Met) variant in a proband and two additional affected relatives, confirming familial transmission (PMID:12216071). Across published series, CDH1 variants include missense changes comprising ~30% of alleles, splice-site variants, and inactivating truncations, reflecting allelic heterogeneity (PMID:16787116). Recurrent germline mutations, such as p.Val832Met and p.Ala634Thr, have been documented in multiple families. These data provide strong genetic support for CDH1 as a causative gene in HDGC.

Functional studies of germline and tumour-associated CDH1 variants have consistently shown loss of E-cadherin mediated cell–cell adhesion and increased invasive behavior. In CHO cell models, expression of p.Ala634Ser, p.Ala634Val, and p.Thr340Ala resulted in defective aggregation and enhanced motility and invasion assays compared with wild-type E-cadherin (PMID:12588804). The cytoplasmic p.Val832Met germline variant similarly failed to mediate adhesion and suppressed invasion in collagen matrix assays (PMID:12944922). Mechanistic investigations revealed that these missense alterations do not trigger β-catenin–dependent transcriptional activation, indicating a primary adhesive deficiency. Additional in vitro analyses demonstrate that mutant E-cadherin variants impair calcium binding and disrupt the structural stability of the extracellular domains. Collectively, these concordant functional assays support a haploinsufficiency mechanism underlying HDGC.

International guidelines recommend CDH1 genetic testing for individuals with HDGC family history, including those with early-onset diffuse gastric carcinoma and lobular breast cancer, to guide risk-reduction strategies and surveillance (PMID:16787116). Prophylactic total gastrectomy is advised for confirmed carriers, significantly reducing gastric cancer incidence in this high-risk population. Cascade testing of first-degree relatives facilitates early detection and intervention. Variant interpretation relies on integrating segregation, population frequency, and functional assay data to classify missense alleles. Functional characterisation of novel CDH1 variants in cell models is recommended to resolve variants of uncertain significance. These measures exemplify how genetic data on CDH1 informs precision prevention in clinical practice.

Loss of functional E-cadherin due to germline CDH1 mutations leads to reduced epithelial cohesion, promoting the discohesive, signet-ring cell morphology characteristic of diffuse gastric carcinoma. The absence of gain-of-function effects and the lack of conflicting genetic or phenotypic associations reinforce a haploinsufficiency model. While in silico predictions may be inconclusive for some missense variants, direct functional assessment reliably distinguishes pathogenic from benign changes. No studies have refuted the CDH1–HDGC association, although the clinical significance of certain missense alleles may remain disputed without functional data. Overall, the genetic and experimental evidence is highly concordant and robust for HDGC. This clear mechanism guides the interpretation of novel CDH1 variants in a diagnostic setting.

The integration of genetic, segregation, and functional data meets ClinGen criteria for a Strong gene–disease association between CDH1 and HDGC. Genetic evidence is supported by multiple independent studies identifying 66 unrelated probands with diverse variant classes and clear familial segregation patterns. Functional evidence includes cell-based adhesion and invasion assays demonstrating loss-of-function across key variants, consistent with a tumor suppressor mechanism. No significant conflicting evidence has emerged to undermine this association. Additional support from epidemiological studies and animal models, while exceeding the scope of published functional assays, further reinforces the role of CDH1 in gastric carcinogenesis. Key Take-home: CDH1 germline testing is clinically actionable for informing risk-reduction interventions in HDGC families.

References

• Expert review of molecular diagnostics • 2003 • Genetic screening for hereditary diffuse gastric cancer. PMID:12647996
• Human molecular genetics • 2003 • Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands. PMID:12588804
• Oncogene • 2003 • The intracellular E-cadherin germline mutation V832 M lacks the ability to mediate cell-cell adhesion and to suppress invasion. PMID:12944922
• International journal of cancer • 2002 • E-cadherin gene variants in gastric cancer families whose probands are diagnosed with diffuse gastric cancer. PMID:12216071
• Future oncology (London, England) • 2006 • Genetics of hereditary diffuse gastric cancer: progress and future challenges. PMID:16787116

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