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Cancer Epidemiol Biomarkers Prev. 2017 Mar;26(3):404-412. doi: 10.1158/1055-9965.EPI-16-0693. Epub 2016 Oct 31.

Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer.

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Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.
Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
University of Colorado School of Medicine, Denver, Colorado.
Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
University of Hawaii Cancer Center, Honolulu, Hawaii.
Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, California.
School of Public Health, University of Washington, Seattle, Washington.
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Centre for Public Health Research, Massey University, Wellington, New Zealand.
Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona.
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.


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.

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