Get access

Cancer Risks for MLH1 and MSH2 Mutation Carriers


  • Communicated by David E. Goldgar

  • Contract grant sponsors: National Cancer Institute, National Institutes of Health (RFA # CA-95—011); Australasian Colorectal Cancer Family Registry (U01 CA097735); Familial Colorectal Neoplasia Collaborative Group (U01 CA074799) [USC]; Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800); Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); Seattle Colorectal Cancer Family Registry (U01 CA074794); University of Hawaii Colorectal Cancer Family Registry (U01 CA074806); National Health and Medical Research Council, Australia (1023434, 400160); The Cancer Council of Victoria, Australia (454695).

Correspondence to: James G. Dowty, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Parkville, Victoria 3010, Australia; E-mail:


We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%–50%) and 47% (36%–60%) for male carriers and 36% (25%–51%) and 37% (27%–50%) for female carriers. Corresponding EC risks were 18% (9.1%–34%) and 30% (18%–45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%–10% and 18% have risks of 90%–100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.