Cancer

Win, Aung Ko; Jenkins, Mark A.; Dowty, James G.; Antoniou, Antonis C.; Lee, Andrew; 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.

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Cancer

Oct 31 2016

By Win, Aung Ko ; Jenkins, Mark A. ; Dowty, James G. ; ...

Source: Cancer Epidemiol Biomarkers Prev. 26(3):404-412.

[PDF-398.65 KB]

English

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Alternative Title:

Cancer Epidemiol Biomarkers Prev

Personal Author:

Win, Aung Ko ; Jenkins, Mark A. ; Dowty, James G. ; Antoniou, Antonis C. ; Lee, Andrew ; ... More +

Description:

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 ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively). Conclusion 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.

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Source:

Cancer Epidemiol Biomarkers Prev. 26(3):404-412. ;

Pubmed ID:

27799157

Pubmed Central ID:

PMC5336409

Document Type:

Journal Article ;

Funding:

HHSN261201000035C/PC,CA/None/None ; U01 CA074799/CA/NCI NIH HHS/United States ; 11174/Cancer Research UK/United Kingdom ; U24 CA074783/CA/NCI NIH HHS/United States ; N01 CN067009/CN/NCI NIH HHS/United States ; ... More +

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	NIHMS827219-supplement-2.docx	docx
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Cancer

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