Abstract B51: Genetic polymorphisms of the UDP-glucuronosyltransferase 2B15 and 2B17 genes are associated with prostate cancer in African American men.

The rate of incidence and mortality from prostate cancer among African American men compared to Caucasian men is more than two-fold higher. Genes related to steroid metabolism have been investigated for their association with prostate cancer etiology. The UDP-glucuronosyltransferase 2B17 (UGT2B17) and UGT2B15 enzymes exhibit specificity for androgen metabolites such as testosterone, dihydrotestosterone (DHT), androsterone (ADT), and androstane-3α,17β-diol (3α-diol) in prostate tissue and cell lines. Copy number variants and SNPs of UGT2B17 and UGT2B15 have been evaluated for prostate cancer risk in Caucasians in several studies but the results have been inconclusive and the studies have included few African Americans subjects. Data from a previous hospital-based case-control study at the Durham Veterans Affairs Medical Center (DVAMC) found that a missense polymorphism UGT2B15D85Y was significantly associated with prostate cancer risk. We hypothesized that functional UGT2B15 and UGT2B17 polymorphisms would show associations for prostate cancer risk. For this study, we selected from the UGT2B15 gene, a panel of eight SNPs; five promoter SNPs, UGT2B15-506 , UGT2B15-818 , UGT2B15-1139 , UGT2B15-1397 , and UGT2B15-1844 that are in high LD with UGT2B15D85Y ; then SNPs UGT2B15T523K , UGT2B153'UTR that are highly linked; and a UGT2B15 distal promoter SNP. From the UGT2B17 gene, UGT2B17V181I was selected. In addition, two cis-acting SNPs were also included that were linked to UGT2B17 expression alone or to the expression of both UGT2B17 and UGT2B15. Genomic DNA samples, from African Americans (142 cases, 138 controls) and Caucasian men (87 cases, 197 controls) accrued at the DVAMC, were genotyped using Sequenom MassArray technology and assays designed by Sequenom online assay tools. To determine the association of the SNPs with prostate cancer cases compared to controls, logistic regression models were used to estimate odd ratios (ORs) under dominant and log-additive models for the minor allele using the homozygous major allele as the reference group. After adjusting for age, race, and BMI, three ( UGT2B15-1139 , UGT2B15-1397 , and UGT2B15-1844 ) of the five promoter SNPs in high LD with UGT2B15D85Y and the UGT2B15 distal promoter SNP were found to be inversely associated with risk for prostate cancer under the log-additive model. Similar results were obtained for UGT2B15T523K and UGT2B153'UTR . In contrast, the minor allele for the cis-acting SNP that is linked to UGT2B17 and UGT2B15 expression was found to be associated with increased risk for prostate cancer. After stratifying for race, only associations of the minor alleles of SNPs UGT2B15T523K (OR = 0.52, 95% CI = 0.30, 0.90) and UGT2B153'UTR (OR = 0.56, 95% CI = 0.36, 0.87) remained significant in African Americans under the log-additive model. Variants of the UGT2B15 gene, UGT2B15T523K and UGT2B153'UTR , were shown for the first time to be associated with prostate cancer risk among African Americans and not Caucasians. Log additive models revealed a dose-dependent association. Moreover, these data suggest that wild type alleles confer increased risk to prostate cancer among African American men. Future studies with larger sample sizes are needed to validate these findings. Citation Format: Cocoa Tucker, Adriana C. Vidal, Joellen M. Schildkraut, Ricardo M. Richardson, Stephen J. Freedland, Cathrine Hoyo, Delores J. Grant. Genetic polymorphisms of the UDP-glucuronosyltransferase 2B15 and 2B17 genes are associated with prostate cancer in African American men. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B51.