Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families

Background & Aims: Germline mutations in CDH1 are known to cause hereditary diffuse gastric cancer (HDGC). Breast and colorectal cancer have also been reported in CDH1-associated HDGC. The purpose of this study was to estimat e the cumulative risk of gastric and breast cancer in CDH1 mutation carrier s. Methods: Family data were collected by member groups of the Internationa l Gastric Cancer Linkage Consortium. Eligible families had at least 3 cases of diffuse gastric cancer, and at least 1 affected member had tested posit ive for a mutation in CDH1. Eleven families met these criteria. We used the pedigree information to estimate penetrance using the MENDEL program. The conditional likelihood of the pedigree was maximized given the phenotype of the pedigree and genotype of the index case at ascertainment. We parameter ized the model in terms of log relative risks for mutation carriers compare d with risks in the general population of the United Kingdom. Noncarriers o f the gene were assumed to develop the disease at population incidence rate s. Results: The estimated cumulative risk of gastric cancer by age 80 years was 67% for men (95% confidence interval [95% CI], 39-99) and 83% for wome n (95% CI, 58-99). For women, the cumulative risk of breast cancer was 39% (95% CI, 12-84). The combined risk of gastric cancer and breast cancer in w omen was 90% by age 80 years. Conclusions: These penetrance estimates shoul d be useful for genetic counseling in multiple-case families. However, they may not apply to individuals with a minimal family history, in whom the ri sks may be lower.