Hereditary Diffuse Gastric Cancer Genetics

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant syndrome predominantly driven by germline mutations in the CDH1 gene, which encodes the cell–cell adhesion molecule E-cadherin. Pathogenic CDH1 variants, most often truncating or splice‐site alterations, disrupt epithelial integrity and confer a lifetime risk of diffuse gastric cancer exceeding 30–50 per cent. Tumourigenesis typically follows a two‐hit model, with a somatic second event—frequently promoter methylation—leading to complete loss of E-cadherin function. Multiple microscopic foci of signet ring cell carcinoma arise in anatomically predilected regions of the stomach, notably the distal antrum and transitional zones, and may remain indolent before invasive progression. Penetrance estimates vary by cohort and ascertainment strategy, but recent data suggest somewhat lower cumulative risks than historic figures. Beyond CDH1, emerging predisposition genes such as PALB2, MAP3K6 and DNA-repair factors have been identified in non-CDH1 families, broadening the genetic architecture of HDGC. Clinical management balances the high efficacy of prophylactic total gastrectomy against its substantial impact on quality of life, while endoscopic surveillance with systematic random biopsies seeks to detect early signet ring cell foci in those delaying surgery. Integrating molecular insights with refined risk estimates informs personalised strategies and underscores the global importance of genetic counselling and early intervention.

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Hereditary Diffuse Gastric Cancer Genetics publication trend

The graph below shows the total number of articles in hereditary diffuse gastric cancer genetics across all publications each year (not limited to Nature Index journals).

Technical terms

Germline mutation: A DNA alteration present in all cells, inherited and transmissible to offspring.

CDH1: The gene encoding E-cadherin, a protein essential for epithelial cell adhesion.

Penetrance: The proportion of individuals with a pathogenic variant who develop the associated disease.

Signet ring cell carcinoma: A subtype of diffuse gastric cancer characterised by cells with prominent mucin vacuoles displacing the nucleus.

Prophylactic gastrectomy: Preventive surgical removal of the stomach to eliminate cancer risk in high-risk individuals.

Second-hit mechanism: A somatic event, such as promoter methylation or loss of heterozygosity, that inactivates the remaining wild-type allele of a tumour suppressor gene.

References

1. Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy. Journal of Clinical Oncology (2023).
2. Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications. Journal of Experimental & Clinical Cancer Research (2023).
3. Comparison of CDH1 Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers. JAMA Oncology (2019).
4. Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study. The Lancet Gastroenterology & Hepatology (2018).
5. Germline Mutations in MAP3K6 Are Associated with Familial Gastric Cancer. PLOS Genetics (2014).
6. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut (2004).
7. Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study. The Lancet Oncology (2022).