Detection of UGT1A10 polymorphisms and their association with orolaryngeal carcinoma risk

Abstract

BACKGROUND UGT1A10 exhibits glucuronidating activity against metabolites of the tobacco smoke carcinogen, benzo(a)pyrene, and is expressed highly in numerous target tissues for tobacco‐related cancers including the upper aerodigestive tract. The current study was conducted to determine the prevalence of genetic polymorphisms in the UGT1A10‐specific region of the UDP‐glucuronosyltransferase family 1A locus and their relationship with risk for orolaryngeal carcinoma. METHODS The authors analyzed UGT1A10‐specific sequences in a population of black, white, and Asian individuals. Ten UGT1A10 alleles were identified by direct sequencing of UGT1A10 sequences amplified by polymerase chain reaction (PCR) using DNA purified from buccal cell swabs that were taken from individual subjects. RESULTS In addition to three silent polymorphisms, three missense polymorphisms were found at codons 139 (Glu > Lys), 240 (Thr > Met), and 244 (Leu > Ile). Using PCR‐restriction fragment length polymorphism analysis of buccal cell DNA, the prevalence of the UGT1A10240Met variant was less than 0.01% in whites and blacks. Similarly, the prevalence of both the UGT1A10139Lys and UGT1A10244Ile variants was less than 0.01% in whites but it was significantly higher (0.04 and 0.05, respectively, P < 0.01) in blacks. None of the missense UGT1A10 variants were found in any of the Asian individuals examined. In a case–control study of black individuals, a significant association with orolaryngeal carcinoma risk was found in persons with at least 1 UGT1A10139Lys allele (crude odds ratio, 0.29 [95% confidence interval, 0.10–0.81]; adjusted odds ratio, 0.20 [95% confidence interval, 0.05–0.87]). No association was observed for the codon 244 (Leu > Ile) polymorphism. CONCLUSIONS The data from the current study show that the UGT1A10 gene has several low‐frequency missense polymorphisms and that the codon 139 polymorphism is an independent risk factor for orolaryngeal carcinoma in blacks. Cancer 2003;98:872–80. © 2003 American Cancer Society. DOI 10.1002/cncr.11587

Functional Characterization of Low-Prevalence Missense Polymorphisms in the UDP-Glucuronosyltransferase 1A9 Gene

“…For the identification of UGT1A9 polymorphisms and determination of prevalence in different racial groups, our population included 253 whites, 164 African Americans, and 59 Asians as described previously (Richie et al, 1997;Park et al, 2000;Elahi et al, 2003). The allele and genotype frequencies for polymorphisms in the CYP1A1, CYP2E1, GSTM1, GSTT1, and GSTP1 genes in this population were similar to those observed in a pooled analysis of more than 15,000 subjects who served as controls in other case-control studies (Garte et al, 2002).…”

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

“…The variant T202I exhibited decreased activity in this system, whereas the M59I change did not result in significant activity change. The only other study focusing on UGT1A10 polymorphisms has examined its role in orolaryngeal carcinoma risk (Elahi et al, 2003). Elahi et al reported six UGT1A10 polymorphisms (including three non-synonymous SNPs) in three racial groups.…”

“…The frequency of both the E139K and L244I amino-acid changes was significantly higher in African Americans compared with Caucasians, and these mutations were absent in Asians. The role of these polymorphisms in orolaryngeal cancer risk was evaluated in 115 African Americans and 115 matched controls (Elahi et al, 2003). Individuals with the 139E allele were found to have a significantly lower risk for orolaryngeal carcinoma, whereas no association was found between cancer and the L244I variant.…”

Smoking and Smokeless Tobacco-Associated Human Buccal Cell Mutations and Their Association with Oral Cancer—A Review

“…The tests for assessing buccal cell changes associated with smoking included procedures that employed PCR (n = 10 articles; refs. 25,26,30,32,35,36,40,41,45,47) and DNA adduct technology (n = 9; refs. 38, 39, 46, 48, 49, 54, 57-59; Table 1).…”