Polymorphisms of the human UDP-glucuronosyltransferase (UGT) 1A7 gene in colorectal cancer

Background: Genetic polymorphisms in the human UDP-glucuconosyltransferase-1A7 (UGTIA7) 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, 13 1, 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 Results: Homozygous wild-type UGT1A7 alleles were present in 20% of normal controls but were only (0) 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% Cl 1.6 4.71); p<0.001). Recombinant expression of UGTIA7 polymorphic cDNA in eukaryotic cell culture showed reduced carcinogen glucuronidation activity in comparison with wild-type UGTIA7. UGTIA7 may therefore 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.