Background: Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. Methods: We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. Results: For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI]=14% to 32%) and 44% (95% CI=28% to 62%) for men and 10% (95% CI=5% to 17%) and 20% (95% CI=11% to 35%) for women; for endometrial cancer, 26% (95% CI=18% to 36%) and 44% (95% CI=30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI=16% to 37%) and 47% (95% CI=32% to 66%) for men and 40% (95% CI=32% to 52%) and 65% (95% CI=53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR=7.6, 95% CI=5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR=25.5, 95% CI=16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR=6.0, 95% CI=3.4 to 10.7).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers. The Author 2009. Published by Oxford University Press.2010
Bibliographical noteFunding Information:
Recruitment, data collection, and genetic testing for the Colon Cancer Family Registry work were supported by the National Cancer Institute, National Institutes of Health under Request for Applications #CA-95-011, and through cooperative agreements with the members of the Colon Cancer Family Registry and principal investigators. The Columbus-area Hereditary Non-Polyposis Colorectal Cancer study performed by the Ohio State University Comprehensive Cancer Center was supported by grants from the National Cancer Institute, National Institutes of Health (R01-CA67941 and -CA16058). The work in Edinburgh was supported by Cancer Research UK (C348/A8896); a center grant from CORE as part of the Digestive Cancer Campaign (www.corecharity.org.uk); Medical Research Council (G0000657-53203); and Scottish Executive Chief Scientist’s Office (K/OPR/2/2/ D333). National Cancer Institute (CA67941 and CA16058 to A.d.l.c. and H.H).