Aung Ko Win, Mark A. Jenkins, James G. Dowty, Antonis C. Antoniou, Andrew Lee, Graham G. Giles, Daniel D. Buchanan, Mark Clendenning, Christophe Rosty, Dennis J. Ahnen, Stephen N. Thibodeau, Graham Casey, Steven Gallinger, Loïc Le Marchand, Robert W. Haile, John D. Potter, Yingye Zheng, Noralane M. Lindor, Polly A. Newcomb, John L. Hopper, Robert J. MacInnis

While high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the USA, Canada and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of and hazard ratio for unidentified major gene mutations, and the variance of the residual polygenic component. We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1= 1 in 1946, MSH2= 1 in 2841, MSH6= 1 in 758, PMS2= 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30-50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age {greater than or equal to}70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively). Unidentified major genes might explain one-third to one-half of the missing heritability of colorectal cancer. Our findings could aid gene discovery and development of better colorectal cancer risk prediction models.