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Polymorphisms of the human UDP-glucuronosyltransferase (UGT) 1A7 gene in colorectal cancer
  1. C P Strassburg1,
  2. A Vogel1,
  3. S Kneip1,
  4. R H Tukey2,
  5. M P Manns1
  1. 1Department of Gastroenterology and Hepatology, Hannover Medical School, 30625 Hannover, Germany
  2. 2Departments of Chemistry and Biochemistry, and Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA
  1. Correspondence to:
    Dr C P Strassburg, Department of Gastroenterology and Hepatology, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany;
    strassburg.christian{at}mh-hannover.de

Abstract

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.

  • UGT1A7
  • xenobiotic metabolism
  • environmental carcinogens
  • colorectal cancer
  • UGT1A gene locus
  • allelic association
  • UGT, UDP-glucuronosyltransferase
  • CRC, colorectal cancer
  • TGGE, temperature gradient gel electrophoresis
  • PhIP, amino-1-methyl-6-phenylimidazo-(4.5-β)-pyridine

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