Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients

Abstract

Germline mutations of the cell adhesion molecule E-cadherin have been shown for the first time to underlie a hereditary diffuse type gastric cancer syndrome (HDGC) in Maori families,1 and subsequently have been reported in HDGC patients of various ethnic origins.2–9 Gastric cancer may also be associated with other hereditary tumour syndromes, which are mainly characterised by carcinomas of other organs. One of these syndromes is the HNPCC syndrome (hereditary nonpolyposis colorectal cancer syndrome), which is caused by germline mutations in DNA mismatch repair genes.10 Furthermore, gastric cancer has been observed in the context of the Li Fraumeni syndrome, a rare cancer syndrome due to germline mutations of the TP53 tumour suppressor gene,11–14 as well as in association with the FAP and Peutz–Jeghers syndrome.15 Despite known molecular genetic causes, contributing to a genetic predisposition to gastric cancer, a considerable number of familial cases have been reported that were not attributable to one of this hereditary syndromes, suggesting that unknown susceptibility genes for gastric cancer might exist. Putative tumour suppressor genes that are commonly inactivated in sporadic gastric cancers, such as the RUNX3 or HPP1 genes, are potential candidate susceptibility genes.16,17 In a previous study, we identified one E-cadherin germline mutation among seven diffuse type familial gastric cancer patients, indicating that in addition to E-cadherin , other genes might be involved in genetic predisposition to the disease in this patient group.4 There were three goals of the present study. First, we aimed to extend our analysis of E-cadherin germline mutations to a higher number of patients, to evaluate the contribution of germline mutations in this gene to German familial and early onset gastric cancer patients and to characterise identified missense mutations for their functional relevance. Secondly, we wished to analyse the role …