A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants

作者：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; Kuery S; Bezieau 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; Capella G; Barnetson R; Porteous M E; Dunlop M G; Farrington S M^*

来源：British Journal of Cancer, 2010, 103(12): 1875-1884.

DOI：10.1038/sj.bjc.6605966

• colorectal cancer
• base excision repair
• MUTYH
• carrier risk estimates
• meta-analysis

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 A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR = 10.8, 95% CI: 5.02-23.2; OR = 6.47, 95% CI: 2.33-18.0; OR = 3.35, 95% CI: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. British Journal of Cancer (2010) 103, 1875-1884. doi:10.1038/sj.bjc.6605966 www.bjcancer.

• 出版日期2010-12-7