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

Accepted version
Peer-reviewed

Type

Article

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Authors

Win, Aung Ko 
Jenkins, Mark A 
Dowty, James G 
Antoniou, Antonis C 

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.

Description

Keywords

Adult, Aged, Colorectal Neoplasms, DNA Glycosylases, DNA Mismatch Repair, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Multifactorial Inheritance, MutL Protein Homolog 1, Mutation, Penetrance, Population Surveillance, Prevalence, Risk Factors

Journal Title

Cancer Epidemiol Biomarkers Prev

Conference Name

Journal ISSN

1055-9965
1538-7755

Volume Title

26

Publisher

American Association for Cancer Research (AACR)
Sponsorship
This work was supported by grant UM1 CA167551 from the National Cancer Institute, National Institutes of Health (NIH) and through cooperative agreements with the following Colon Cancer Family Registry (CCFR) centers: Australasian Colorectal Cancer Family Registry (U01/U24 CA097735), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (U01/U24 CA074794), and USC Consortium Colorectal Cancer Family Registry (U01/U24 CA074799). For further information regarding funding, please visit the publisher's website.