Identification and Survival of Carriers of Mutations in DNA Mismatch-Repair Genes in Colon Cancer

BACKGROUND The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease. METHODS Without preselection and regardless of family history, we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer. We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival. RESULTS There were 38 mutations among the 870 participants (4 percent): 15 mutations in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6 percent) and women (3 percent) differed significantly (P