期刊
BRITISH JOURNAL OF CANCER
卷 103, 期 12, 页码 1875-1884出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6605966
关键词
colorectal cancer; base excision repair; MUTYH; carrier risk estimates; meta-analysis
类别
资金
- Cancer Research UK [C348/A3758, C348/A8896, C31250/A10107]
- Scottish Government Chief Scientist Office [K/OPR/2/2/D333, CZB/4/94, CZB/4/449]
- Medical Research Council [G0000657-53203]
- CORE
- Foundation Dr Henri Dubois-Ferriere Dinu Lipatti
- Regional Hospital Clinical Research Program
- Regional Council of Pays de la Loire
- Groupement des Entreprises Francaises dans la LUtte contre le Cancer
- Association Anne de Bretagne Genetique
- Ligue Regionale Contre le Cancer
- Swedish Cancer Society
- Swedish Research Council
- Stockholm Cancer Foundation
- Ministerio de Educacion y Ciencia [SAF09-7319]
- Spanish Networks RTICCC [RD06/0020/1050, 1051]
- Instituto de Salud Carlos III [FIS PI03/0114, FIS 05/1006, CIBERESP]
- Cancer Research UK [11021] Funding Source: researchfish
- Chief Scientist Office [CZB/4/449] Funding Source: researchfish
- Medical Research Council [MC_U127527198] Funding Source: researchfish
- The Francis Crick Institute
- Cancer Research UK [10119, 10124] Funding Source: researchfish
- MRC [MC_U127527198] Funding Source: UKRI
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 A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR = 10.8, 95% CI: 5.02-23.2; OR = 6.47, 95% CI: 2.33-18.0; OR = 3.35, 95% CI: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.com Published online 9 November 2010 (C) 2010 Cancer Research UK
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