Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer.
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Authors
Win, Aung Ko
Jenkins, Mark A
Dowty, James G
Giles, Graham G
Buchanan, Daniel D
Clendenning, Mark
Rosty, Christophe
Ahnen, Dennis J
Thibodeau, Stephen N
Casey, Graham
Gallinger, Steven
Le, Marchand Loïc
Haile, Robert W
Potter, John D
Zheng, Yingye
Lindor, Noralane M
Newcomb, Polly A
Hopper, John L
MacInnis, Robert J
Publication Date
2017-03Journal Title
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
ISSN
1055-9965
Publisher
American Association for Cancer Research
Volume
26
Pages
404-412
Language
English
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Win, A. K., Jenkins, M. A., Dowty, J. G., Antoniou, A., Lee, A. J., Giles, G. G., Buchanan, D. D., et al. (2017). Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer.. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 26 404-412. https://doi.org/10.1158/1055-9965.epi-16-0693
Abstract
BACKGROUND: While 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 USA, 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 and hazard ratio 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 1946, MSH2= 1 in 2841, 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 30-50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age {greater than or equal to}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.
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.
Identifiers
External DOI: https://doi.org/10.1158/1055-9965.epi-16-0693
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262022
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