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Previous Volume 339:511-518 August 20, 1998 Number 8 Next

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ABSTRACT

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 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1.

Conclusions Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.

Source Information

From the Departments of Human Genetics (J.T.W., P.M.K., H.K., A.M., R.F.), Gastroenterology (H.F.A.V.), and Medical Statistics (A.H.Z.) and the Clinical Genetics Center (C.T.), Leiden University Medical Center, Leiden, the Netherlands; the Foundation for the Detection of Hereditary Tumors, Leiden, the Netherlands (H.F.A.V.); and the Unit of Medical Genetics, Norwegian Radium Hospital, Oslo, Norway (P.M.). Other authors were Fred Menko, M.D., Ph.D. (University Hospital Vrije Universiteit, Amsterdam, the Netherlands), Babs Taal, M.D., Ph.D. (Netherlands Cancer Institute, Amsterdam, the Netherlands), Fokko Nagengast, M.D., Ph.D., and Han Brunner, M.D., Ph.D. (Nijmegen University Hospital, Nijmegen, the Netherlands), Jan Kleibeuker, M.D., Ph.D., and Rolf Sijmons, M.D. (University Hospital Groningen, Groningen, the Netherlands), Gerrit Griffioen, M.D., Ph.D., Annette Bröcker-Vriends, M.D., Ph.D., Egbert Bakker, Ph.D., and Inge van Leeuwen-Cornelisse, B.S. (Leiden University Medical Center, Leiden, the Netherlands), Anne Meijers-Heijboer, M.D., Dick Lindhout, M.D., Ph.D., and Martijn Breuning, M.D., Ph.D. (Erasmus University, Rotterdam, the Netherlands), Jan Post, M.D. (Clinical Genetics Center Utrecht, Utrecht, the Netherlands), Cees Schaap, M.D. (Clinical Genetics Center Maastricht, Maastricht, the Netherlands), Jaran Apold, M.D., Ph.D. (Haukeland University Hospital, Bergen, Norway), Ketil Heimdal, Ph.D. (Norwegian Radium Hospital, Oslo, Norway), Lucio Bertario, M.D., Ph.D. (Istituto Nazionale Tumori, Milan, Italy), Marie Luise Bisgaard, M.D. (Danish Hereditary Nonpolyposis Colorectal Cancer Registry, Hvidovre Hospital, Hvidovre, Denmark), and Petr Goetz, M.D., Ph.D. (Charles University, Prague, Czech Republic).This work is dedicated to the memory of Dr. P. Meera Khan.

Address reprint requests to Dr. Vasen at the Foundation for the Detection of Hereditary Tumors, Rijnsburgerweg 10, Poortgebouw Zuid, 2333 AA Leiden, the Netherlands.

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