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Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer.
- Source :
-
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology [Cancer Epidemiol Biomarkers Prev] 2017 Mar; Vol. 26 (3), pp. 404-412. Date of Electronic Publication: 2016 Oct 31. - Publication Year :
- 2017
-
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 .<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Adult
Aged
Colorectal Neoplasms genetics
Female
Humans
Male
Middle Aged
MutL Protein Homolog 1 genetics
Mutation
Population Surveillance
Prevalence
Risk Factors
Colorectal Neoplasms epidemiology
DNA Glycosylases genetics
DNA Mismatch Repair
Genetic Predisposition to Disease
Multifactorial Inheritance
Penetrance
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7755
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 27799157
- Full Text :
- https://doi.org/10.1158/1055-9965.EPI-16-0693