E-CADHERIN GERMLINE MUTATIONS IN FAMILIAL GASTRIC-CANCER

The identification of genes predisposing to familial cancer is an esse ntial step towards understanding the molecular events underlying tumor igenesis and is critical for the clinical management of affected famil ies. Despite a declining incidence, gastric cancer remains a major cau se of cancer death worldwide(1), and about 10% of cases show familial clustering(2,3), The relative contributions of inherited susceptibilit y and environmental effects to familial gastric cancer are poorly unde rstood because little is known of the genetic events that predispose t o gastric cancer. Here we describe the identification of the gene resp onsible for early-onset, histologically poorly differentiated, high gr ade, diffuse gastric cancer(4) in a large kindred from New Zealand (Ao tearoa), Genetic linkage analysis demonstrated significant Linkage to markers flanking the gene for the calcium-dependent cell-adhesion prot ein E-cadherin. Sequencing of the E-cadherin gene revealed a G-->T nuc leotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product, Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas(5). U nderexpression of E-cadherin is a prognostic marker of poor clinical o utcome in many tumour types(6), and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour ce lls(7,8). The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cance r families, In one family a frameshift mutation,vas identified in exon 15, and in a second family a premature stop codon interrupted exon 13 , These results describe, to our knowledge for the first time, a molec ular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.