CLINICAL FINDINGS WITH IMPLICATIONS FOR GENETIC TESTING IN FAMILIES WITH CLUSTERING OF COLORECTAL-CANCER

Background Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH 1, PIMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolypo sis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mut ations in families suspected of having hereditary nonpolyposis colorec tal cancer and evaluated whether clinical findings can predict the out come of genetic testing. Methods We used denaturing gradient gel elect rophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with fa miliar clustering of colorectal cancer or other cancers associated wit h hereditary nonpolyposis colorectal cancer. Information on the site o f cancer, the age at diagnosis, and the number of affected family memb ers was obtained from all families. Results Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors as sociated with these mutations were early age at diagnosis of colorecta l cancer, the occurrence in the kindred of endometrial cancer or tumor s of the small intestine, a higher number of family members with color ectal or endometrial cancer, the presence of multiple colorectal cance rs or both colorectal and endometrial cancers in a single family membe r, and fulfillment of the Amsterdam criteria for the diagnosis of here ditary nonpolyposis colorectal cancer (at least three family members i n two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be di agnosed before the age of 50 in at least one family member; and famili al adenomatous polyposis must be ruled out). Multivariate analysis sho wed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in t he kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estima ting the likelihood of a mutation in MSH2 and MLH1. Conclusions Assess ment of clinical findings can improve the rate of detection of mutatio ns of DNA mismatch-repair genes in families suspected of having heredi tary nonpolyposis colorectal cancer. (N Engl J Med 1998;339:511-8.) (C )1998, Massachusetts Medical Society.