Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer
Published Date:Oct 31 2016
Source:Cancer Epidemiol Biomarkers Prev. 26(3):404-412.
Pubmed Central ID:PMC5336409
U01 CA074799/CA/NCI NIH HHS/United States
U24 CA074783/CA/NCI NIH HHS/United States
N01 CN067009/CN/NCI NIH HHS/United States
R01 CA170122/CA/NCI NIH HHS/United States
U24 CA074794/CA/NCI NIH HHS/United States
U24 CA097735/CA/NCI NIH HHS/United States
U01 CA074794/CA/NCI NIH HHS/United States
HHSN261201300012I/CA/NCI NIH HHS/United States
N01PC35142/CA/NCI NIH HHS/United States
HHSN261201000035I/CA/NCI NIH HHS/United States
HHSN261201000034C/CA/NCI NIH HHS/United States
U01 CA097735/CA/NCI NIH HHS/United States
UM1 CA167551/CA/NCI NIH HHS/United States
U58 DP003862/DP/NCCDPHP CDC HHS/United States
U01 CA074783/CA/NCI NIH HHS/United States
U24 CA074799/CA/NCI NIH HHS/United States
U24 CA074800/CA/NCI NIH HHS/United States
U01 CA074800/CA/NCI NIH HHS/United States
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.
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.
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).
Unidentified major genes might explain one-third to one-half of the missing heritability of colorectal cancer.
Our findings could aid gene discovery and development of better colorectal cancer risk prediction models.
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