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A Large-scale Meta-analysis to Refine Colorectal Cancer Risk Estimates Associated with MutYH Variants
source: British Journal of Cancer
year: 2010
authors: Theodoratou E, Campbell H, Tenesa A, Houlston R, Webb E, Lubbe S, Broderick P, Gallinger S, Croitoru E M, Jenkins M A, Win A K, Cleary S P, Koessler T, Pharoah P D, Küry S, Bézieau S, Buecher B, Ellis N A, Peterlongo P, Offit K, Aaltonen L A, Enholm S, Lindblom A, Zhou X L, Tomlinson I P, Moreno V, Blanco I, Capellà G, Barnetson R, Porteous M E, Dunlop M G, Farrington S M
summary/abstract:BACKGROUND:
defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk.
METHODS:
MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study.
RESULTS:
all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77).
CONCLUSIONS:
overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers
DOI: 10.1038/sj.bjc.6605966
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