Abstract 3582: Genetic polymorphisms in NAT2 gene influence overall survival in bladder cancer patients

Abstract

Abstract Aromatic amines are involved in the etiology of bladder cancer and these compounds are acetylated by N-acetyltransferase 1 (NAT1) and 2 (NAT2). Epidemiological studies have shown that the slow NAT2 acetylator phenotype is associated with increased risk of bladder cancer. Although several studies have shown an association between bladder cancer risk and SNPs in NAT2, the impact on survival has not been established. Because SNPs are innate characteristics of individuals, we hypothesize that their presence could have an effect even after tumor resection and, thus, be useful as prognostic markers. In order to investigate this possibility, we examined 5 SNPs in NAT2 gene (rs1041983, rs1801280, rs1799931, rs1495741, rs12545528) and investigated their impact on overall survival (OS). The study population comprised the cohort of new histologically confirmed cases of bladder cancers treated in the urology departments of the S. Giovanni Battista Hospital in Turin. Vital status ascertainment was carried out through linkage with the local town offices. Blood samples and questionnaires of 331 subjects were collected before therapy. White blood cell DNA was purified from stored blood samples. Polymorphic sites were genotyped by 5′Nuclease assay (TaqMan) with fluorogenic Minor Groove Binder probes. Subjects’ phenotype was estimated using a standard approach based on the combination of two polymorphisms: rs1041983 and rs1801280; we also estimated phenotype from SNP rs1495741 (Garcia-Closas et al. 2011). For each SNP we calculated crude and adjusted (by age, stage, grading and therapy) Hazard Ratios (HR) and the corresponding 95% Confidence Interval (95% CI) using the Cox proportional-hazard regression model for the co-dominant and per-allele model. Stratified analyses by kind of therapy and tumour type were also performed. We computed the phase of the haplotype using PHASE 2.1: for each haplotype we computed HR, comparing subjects carrying 2, 1 or 0 copies of the same haplotype. The rs1799931 and the rs1801280 variant alleles, which lead to reduced N-acetyltransferase activity and/or reduced protein stability, were significantly associated with a decreased OS (HR: 4.54; 95% CI: 1,78-11,61 and HR: 1.43; 95% CI: 1,04-1,96 adjusted per allele model, respectively); in contrast variant alleles of SNPs which do not seem to modify the protein activity (rs12545528 non-coding and rs1041983 silent) were significantly associated with an increased OS (HR: 0.68; 95% CI: 0,49-0,96 and HR: 0.58; 95% CI: 0,40-0,85 per allele model, respectively). Similar observations were made when the cases were stratified into papillary and non-papillary tumours or stratified by kind of therapy. Haplotype analysis confirmed the results described above not providing any other indication. In conclusion, NAT2 rs1799931 and rs1801280 functional SNPs can be considered as potential prognostic factors for the survival of patients with bladder cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3582. doi:1538-7445.AM2012-3582