Human Molecular Genetics, Vol 8, 607-610, Copyright © 1999 by Oxford University Press
FM Richards, SA McKee, MH Rajpar, TR Cole, DG Evans, JA Jankowski, C McKeown, DS Sanders and ER Maher
Inherited mutations in the E-cadherin gene ( CDH1 ) were described recently
in three Maori kindreds with familial gastric cancer. Familial gastric
cancer is genetically heterogeneous and it is not clear what proportion of
gastric cancer susceptibility in non-Maori populations is due to germline
CDH1 mutations. Therefore, we screened eight familial gastric cancer
kindreds of British and Irish origin for germline CDH1 mutations, by SSCP
analysis of all 16 exons and flanking sequences. Each family contained: (i)
two cases of gastric cancer in first degree relatives with one affected
before age 50 years; or (ii) three or more cases of gastric cancer. Novel
germline CDH1 mutations (a nonsense and a splice site) were detected in two
families (25%). Both mutations were predicted to truncate the E-cadherin
protein in the signal 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 CDH1 gene cause familial gastric cancer in
non-Maori populations. However, only a minority of familial gastric cancers
can be accounted for by CDH1 mutations. 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.
ARTICLES
Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer
Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham, The Medical School, Birmingham B15 2TT, UK.
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