journal contribution
posted on 2023-03-31, 13:41 authored by 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 We used modified segregation analysis to fit a range of genetic models to the observed colorectal cancer family histories for the proband and their first-degree relatives.
Funding
National Cancer Institute
Australasian Colorectal Cancer Family Registry
Colon Cancer Studies
Fred Hutchinson Cancer Research Center
Surveillance, Epidemiology and End Results
University of Southern California
California Department of Public Health
Centre for Research Excellence
NHMRC
Cancer Research UK Senior Research
History
ARTICLE ABSTRACT
Background: Although 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.Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, 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 HR for unidentified major gene mutations, and the variance of the residual polygenic component.Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, 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% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.
