Background: Gastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear.
Aims: To examine the frequency of CDH1 germline mutations in a population-based series of early-onset gastric cancer (EOGC <50 years old).
Methods: 211 cases of EOGC were identified in Central-East Ontario region from 1989 to 1993, with archival material and histological confirmation of non-intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single-strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E-cadherin (HECD-1) using immunohistochemistry.
Results: 1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30-year-old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early-onset isolated cell gastric cancer.
Conclusion: This is the first population-based study, in a low-incidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2–3% of EOCG cases in North Americans may be owing to high-risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.
- DGC, diffuse-type gastric cancer
- EOGC, early-onset gastric cancer
- HDGC, hereditary diffuse gastric cancer
- IGCLC, International Gastric Cancer Linkage Consortium
- PCR, polymerase chain reaction
- SSCP, single-strand conformation polymorphism
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Published Online First 26 June 2006
Funding: JTB was supported by the Clinician Investigator Program of the University of British Columbia, the National Cancer Institute of Canada-Terry Fox Foundation Post MD Biomedical Research Fellowship and by the Pathology and Laboratory Medicine of the University of Toronto. DGH is a Michael Smith Foundation Scholar for Health Research.
Competing interests: None.