Clinical Findings with Implications for Genetic Testing in Families with Clustering of Colorectal Cancer

作者：Juul Wijnen, Hans F. A. Vasen, P. Meera Khan, Aeilko Having Zwinderman, Heleen M. van der Klift, Adri Mulder, Carli M.J. Tops, Pål Møller, Riccardo Fodde, Fred H. Menko, Babs G. Taal, Fokko M. Nagengast, Han G. Brunner, Jan H. Kleibeuker, Rolf H. Sijmons, Gerrit Griffioen, Annette H. J. T. Bröcker‐Vriends, Egbert Bakker, Inge van Leeuwen‐Cornelisse, Anne Meijers-Heijboer, Dick Lindhout, Martijn H. Breuning, Jan G. Post, Cees Schaap, Jaran Apold, Ketil Heimdal, Lucio Bertario, Marie Luise Bisgaard, P Goetz · 发表于：New England Journal of Medicine · 年份：1998 · DOI：10.1056/nejm199808203390804 · 被引用次数：397 · 研究领域：Genetic factors in colorectal cancer、Colorectal Cancer Screening and Detection、Cancer Genomics and Diagnostics

BACKGROUND: Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing. METHODS: We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families. RESULTS: Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50...