Originally published as JCO Early Release 10.1200/JCO.2004.02.033 on October 13 2004

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Lower Incidence of Colorectal Cancer and Later Age of Disease Onset in 27 Families With Pathogenic MSH6 Germline Mutations Compared With Families With MLH1 or MSH2 Mutations: The German Hereditary Nonpolyposis Colorectal Cancer Consortium

From the Department of Surgical Research, Dresden University of Technology, Dresden; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig; Department of Medical Genetics, University of Munich, Munich; Institute of Human Genetics, University Hospital Bonn, Bonn; Department of Surgery, Heinrich-Heine-University, Düsseldorf, Düsseldorf; Department of Medicine, Knappschaftskrankenhaus, Ruhr University Bochum, Bochum; Department of Pathology, Division of Molecular Pathology, University of Heidelberg, Heidelberg; Institute of Pathology, Klinikum Kassel, Kassel, Germany

Address reprint requests to Jens Plaschke, PhD, Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Dresden University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany; e-mail: plaschke{at}rcs.urz.tu-dresden.de

PURPOSE: The aim of the study was the analysis of the involvement and phenotypic manifestations of MSH6 germline mutations in families suspected of hereditary nonpolyposis colorectal cancer (HNPCC).

PATIENTS AND METHODS: Patients were preselected among 706 families by microsatellite instability, immunohistochemistry, and/or exclusion of MLH1 or MSH2 mutations and were subjected to MSH6 mutation analysis. Clinical and molecular data of MSH6 mutation families were compared with data from families with MLH1 and MSH2 mutations.

RESULTS: We identified 27 families with 24 different pathogenic MSH6 germline mutations, representing 3.8% of the total of the families, and 14.7% of all families with DNA mismatch repair (MMR) gene mutations (n = 183). The median age of onset of colorectal cancer in putative mutation carriers was 10 years higher for MSH6 (54 years; 95% CI, 51 to 56) compared with MLH1 and MSH2 (44 years; 95% CI, 43 to 45; log-rank test, P = .0038). Relative to other malignant tumors, colorectal cancer was less frequent in MSH6 families compared with MLH1 and MSH2 families (Fisher's exact test, P < .001). In contrast, the frequency of non–HNPCC-associated tumors was increased (Fisher's exact test, P < .001).

CONCLUSION: Later age of disease onset and lower incidence of colorectal cancer may contribute to a lower proportion of identified MSH6 mutations in families suspected of HNPCC. However, in approximately half of these families, at least one patient developed colorectal or endometrial cancer in the fourth decade of life. Therefore, a surveillance program as stringent as that for families with MLH1 or MSH2 mutations is recommended.

Supported by the Verbundprojekt "Familiärer Darmkrebs" of the Deutsche Krebshilfe (DKH, German Cancer Aid).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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• MSH6 Mutations in Hereditary Nonpolyposis Colon Cancer: Another Slice of the Pie
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  JCO 2004 22: 4449-4451 [Full Text]

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