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 A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR10.8, 95% CI: 5.02-23.2; OR6.47, 95% CI: 2.33-18.0; OR3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR1.16, 95% CI: 1.00-1.34) and Y179C alone (OR1.34, 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.
Original language | English (US) |
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Pages (from-to) | 1875-1884 |
Number of pages | 10 |
Journal | British Journal of Cancer |
Volume | 103 |
Issue number | 12 |
DOIs | |
State | Published - Dec 7 2010 |
Funding
We thank all the study participants and the many colleagues world wide who contributed to recruitment. We are particularly grateful to Ruth Wilson, Rosa Bisset, Nicola Cartwright and Gisela Johnstone, and all those who contributed to recruitment, data collection and data curation for the Scottish COGS and SOCCS studies. This work was supported by grants from Cancer Research UK (C348/A3758, C348/A8896), Scottish Government Chief Scientist Office (K/OPR/2/2/D333, CZB/4/94, CZB/4/449); Medical Research Council (G0000657-53203); Centre Grant from CORE as part of the Digestive Cancer Campaign (http://www.corecharity. org.uk). ET is funded by a Cancer Research UK Fellowship C31250/ A10107. The work at the Institute of Cancer Research is supported grants from Cancer Research UK (supported by Bobby Moore), Steven Lubbe is supported by a Cancer Research UK PhD Studentship. The work in Canada was made possible through collaboration and cooperative agreements with the Colon Cancer
Keywords
- MUTYH
- base excision repair
- carrier risk estimates
- colorectal cancer
- meta-analysis
ASJC Scopus subject areas
- Oncology
- Cancer Research