Human Molecular Genetics, 2003, Vol. 12, No. 5 575-582
© 2003 Oxford University Press
Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands
1Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), 4200 Porto, Portugal, 2Cancer Genomics Program, Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Addenbrooke's Hospital, Cambridge CB2 2XZ, UK, 3Faculdade de Medicina, Hospital de S. João, 4200 Porto, Portugal, 4Laboratory of Experimental Cancerology, UZG, B-9000 Ghent, Belgium, 5Service of Applied Genetics, Institute of Biology and Molecular Medicine, B-6041 Gosselies, Belgium, 6Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham, The Medical School, Birmingham B15 2TT, UK, 7Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA, 8Istituto Policattedra di Scienze Chirurgiche, Universita degli Studi di Siena, 53100 Siena, Italy and 9Department of Pathology and Laboratory Medicine, University of British Columbia Vancouver, Canada
Received November 19, 2002; Accepted December 20, 2002
E-cadherin is involved in the formation of cell-junctions and the maintenance of epithelial integrity. Direct evidence of E-cadherin mutations triggering tumorigenesis has come from the finding of inactivating germline mutations of the gene (CDH1) in hereditary diffuse gastric cancer (HDGC). We screened a series of 66 young gastric cancer probands for germline CDH1 mutations, and two novel missense alterations together with an intronic variant were identified. We then analysed the functional significance of the two exonic missense variants found here as well as a third germline missense variant that we previously identified in a HGDC family. cDNAs encoding either the wild-type protein or mutant forms of E-cadherin were stably transfected into CHO (Chinese hamster ovary) E-cadherin-negative cells. Transfected cell-lines were characterized in terms of aggregation, motility and invasion. We show that a proportion of apparently sporadic early-onset diffuse gastric carcinomas are associated with germline alterations of the E-cadherin gene. We also demonstrate that a proportion of missense variants are associated with significant functional consequences, suggesting that our cell model can be used as an adjunct in deciding on the potential pathogenic role of identified E-cadherin germline alterations.
* To whom correspondence should be addressed. Tel: +0044 1223 3319 89; Fax: +0044 1223 3317 53; Email: cc234{at}cam.au.uk and Tel: +351 225570764; Fax: +351 225570799; Email: rseruca{at}ipatimup.pt
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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