Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer

Inherited mutations in the E-cadherin gene (CDH1) were described recently i n three Maori kindreds with familial gastric cancer, Familial gastric cance r is genetically heterogeneous and it is not clear what proportion of gastr ic cancer susceptibility in non-Maori populations is due to germline CDH1 m utations. Therefore, we screened eight familial gastric cancer kindreds of British and Irish origin for germline CDH1 mutations, by SSCP analysis of a ll 16 exons and flanking sequences. Each family contained: (i) two cases of gastric cancer in first degree relatives with one affected before age 50 y ears; or (ii) three or more cases of gastric cancer, Novel germline CDH1 mu tations (a nonsense and a splice site) were detected in two families (25%). Both mutations were predicted to truncate the E-cadherin protein in the si gnal peptide domain, In one family there was evidence of non-penetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to six cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years, We have confirmed that germline mutations in the CD H1 gene cause familial gastric cancer in non-Maori populations. However, on ly a minority of familial gastric cancers can be accounted for by CDH1 muta tions. Loss of E-cadherin function has been implicated in the pathogenesis of sporadic colorectal and other cancers, and our findings provide evidence that germline CDH1 mutations predispose to early onset colorectal cancer. Thus, CDH1 should be investigated as a cause of inherited susceptibility to both gastric and colorectal cancers.