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

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.

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

“…These findings were based on a case-control study composed of 210 Caucasian controls and 78 cases with colorectal cancer recruited in the same area. 70 Imbalance of the UGT1A7 genotypes was noted in the control group and allele frequencies were significantly different compared to the study of Vogel et al, 69 although subjects of both studies were recruited in the same geographical region. The rationale of studying UGT1A7 in relation with colorectal cancer is mostly based on the role of this enzyme in the metabolism and detoxification of dietary heterocyclic amines.…”

“…However, no association with this genotype was revealed in this study. Similarly, the UGT1A7*3/*3 allele was not associated with colorectal cancer in the study conducted by Strassburg et al, 70 although heterozygous genotypes containing the UGT1A7*3 allele (*1/*3 and *2/ *3) were associated with an approximately two-fold increased risk of developing colorectal cancer (Table 3). These findings were based on a case-control study composed of 210 Caucasian controls and 78 cases with colorectal cancer recruited in the same area.…”

“…Recent studies revealed that specific genetic alterations in UGT genes could contribute to modify the risk factor of developing cancer. [66][67][68][69][70][71][72] The first series of studies were case-control studies of breast cancer patients, in which the role of UGT1A1 as a candidate gene was examined ( Table 3). The hypothesis tested was that constitutive alterations in UGTs involved in the inactivation of estradiol and catechol reactive metabolites could modify estrogen exposure and consequently estrogen-related cancer risk.…”

“…Recent findings suggest that metabolic alterations may actually determine the degree of exposure of an individual to toxic or carcinogenic substances over a long time period and may contribute to modify one's susceptibility to diseases such as cancer. [65][66][67][68][69][70][71][72][73] This review is focused on recent work in the area of the pharmacogenomics of human UGTs. The following topics will be covered: (i) overview of human UGT enzymes; (ii) description of polymorphic human UGT enzymes; (iii) pharmacogenomic phenomena involving polymorphic UGT enzymes in drug response and (iv) pharmacogenomic phenomena involving polymorphic UGT enzymes in cancer.…”

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

“…Black bars represent the exons within the region. Arrows highlight variants previously shown to be associated with human-health phenotypes in either multiple human subject studies or in individual association studies involving more than 100 human subjects; these include the UGT1A8*2 allele, 70,71 the three non-synonymous coding SNPs in UGT1A7 (*2,*3,*10), 69,72,73,81,82 two nsSNPs in UGT1A6 (*2,*3), 67,68,70 rs887829 -the SNP revealing the strongest association with tranilast-induced hyperbilirubinemia, 28 and the UGT1A1*6 allele. 10,24,25,[50][51][52][53][54][55][56][57][83][84][85][86][87] Figure 4 Two-point LD maps for variants of UGT1A1, UGT1A6, and UGT1A9 mapped by population.…”