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

Theodoratou, E; Campbell, H; Tenesa, A; Houlston, R; Webb, E

; Lubbe, S; Broderick, P; Gallinger, S; Croitoru, E; Jenkins, M; +22 more...Win, A; Cleary, S; Koessler, T; Pharoah, P; Küry, S; Bézieau, S; Buecher, B; Ellis, N; Peterlongo, P; Offit, K; Aaltonen, L; Enholm, S; Lindblom, A; Zhou, X; Tomlinson, I; Moreno, V; Blanco, I; Capellà, G; Barnetson, R; Porteous, M; Dunlop, M; Farrington, S and (2010) A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. British journal of cancer, 103 (12). pp. 1875-1884. ISSN 0007-0920 DOI: 10.1038/sj.bjc.6605966

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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 A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89)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.