Polymorphisms of the human UDP-glucuronosyltransferase ( UGT) 1A7 gene in colorectal cancer.
BACKGROUND: Genetic polymorphisms in the human UDP-glucuronosyltransferase-1A7 (UGT1A7) gene are detected and significantly correlated with sporadic colorectal carcinoma. UGT1A7, which has recently been demonstrated to glucuronidate environmental carcinogens, is now implicated as a cancer risk gene. A silent mutation at codon 11 and missense mutations at codons 129, 131, and 208 lead to the description of three polymorphic alleles designated UGT1A7*2, UGT1A7*3, and UGT1A7*4. METHODS: UGT1A7 polymorphisms were analysed by polymerase chain reaction amplification and sequencing, as well as temperature gradient gel electrophoresis in 210 healthy blood donors and 78 subjects with colorectal cancer. RESULTS: Homozygous wild-type UGT1A7 alleles were present in 20% of normal controls but were only detected in 9% of patients with colorectal carcinoma (odds ratio (OR) 0.39 (95% confidence interval (CI) 0.17-0.92); p=0.03). Analysis of individual polymorphic alleles identified a highly significant association between the presence of UGT1A7*3 alleles and colorectal cancer (OR 2.75 (95% CI 1.6 - 4.71); p<0.001). Recombinant expression of UGT1A7 polymorphic cDNA in eukaryotic cell culture showed reduced carcinogen glucuronidation activity in comparison with wild-type UGT1A7. UGT1A7 may therefore represent a modifier gene in colorectal carcinogenesis. CONCLUSION: We have identified a potential novel risk factor in sporadic colorectal cancer which may contribute to the identification of risk groups and to the elucidation of factors involved in colon carcinogenesis.[1]References
- Polymorphisms of the human UDP-glucuronosyltransferase (UGT) 1A7 gene in colorectal cancer. Strassburg, C.P., Vogel, A., Kneip, S., Tukey, R.H., Manns, M.P. Gut (2002) [Pubmed]
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