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. 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

Aung Ko Win  1 , Mark A Jenkins  1 , James G Dowty  1 , Antonis C Antoniou  2 , Andrew Lee  2 , Graham G Giles  1   3 , Daniel D Buchanan  1   4 , Mark Clendenning  4 , Christophe Rosty  5 , Dennis J Ahnen  6 , Stephen N Thibodeau  7 , Graham Casey  8 , Steven Gallinger  9 , Loïc Le Marchand  10 , Robert W Haile  11 , John D Potter  12   13   14 , Yingye Zheng  12   13 , Noralane M Lindor  15 , Polly A Newcomb  12   13 , John L Hopper  1 , Robert J MacInnis  16   3
Affiliations

Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Aung Ko Win et al. Cancer Epidemiol Biomarkers Prev. 2017 Mar.

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.

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Conflict of interest statement

DISCLOSURE

The authors have no conflict of interest to declare with respect to this manuscript.

Figures

Figure 1
Figure 1
Amount of polygenic variance explained by the hypothetical unidentified major genes component (dark grey) and the polygenic component (white) for each 10-year age group.
See this image and copyright information in PMC

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References

    1. Taylor DP, Burt RW, Williams MS, Haug PJ, Cannon-Albright LA. Population-Based Family History-Specific Risks for Colorectal Cancer: A Constellation Approach. Gastroenterology. 2010;138:877–85. - PMC - PubMed
    1. Rustgi AK. The genetics of hereditary colon cancer. Genes Dev. 2007;21:2525–38. - PubMed
    1. Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer. 2015;15:181–94. - PubMed
    1. Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet. 2009;41:112–7. - PubMed
    1. Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat. 2009;30:197–203. - PubMed

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