557 POLYMORPHISMS IN DNA REPAIR GENES MODIFY SURVIVAL OF BLADDER CANCER PATIENTS

Abstract

INTRODUCTION AND OBJECTIVES: A role of genetic variability in DNA repair genes in response to therapies and survival has been reported for lung cancer but not for bladder cancer. Aim of the present study is to investigate the association between 28 SNPs in 8 different DNA repair genes and survival from bladder cancer. METHODS: The study population included all the newly diagnosed, histologically confirmed cases (456 patients) of bladder cancers registered at one single hospital during the years 1994- 2008. All subjects were men, aged 40-75 years and living in the Turin metropolitan area. Before any treatment, a trained interviewer used a detailed questionnaire to conduct a face-to-face interview with patients on their history of tobacco smoking, occupational history, a 22-item food frequency questionnaire and a 24-h medication use recall. The type of therapy (BCG, chemotherapy, radiotherapy, etc) was recorded through the perusal of clinical records, in collaboration with urologists. We selected 28 SNPs in 8 different DNA repair genes because: 1) they have been associated with bladder cancer risk in previous studies and/or 2) they cause amino acidic substitution and/or 3) they are tagging SNPs. For each SNP we estimated the Hazard Ratios (HR) and 95% Confidence Interval (95% CI). We reconstructed haplotypes and imputed the phase by using a Bayesian method. RESULTS: 156 patients died during observation time. Median time of survival was 5.83 years. Variant alleles of five different polymorphisms in XRCC1 gene conferred a better survival, only among patients treated with chemotherapy (rs915927 adjHR 0.37 (95% CI 0.19-0.75); rs76507 adjHR 0.46 (95% CI 0.25-0.84); rs2854501 adjHR 0.34 (95% CI 0.15-0.73); rs2854509 adjHR 0.27 (95% CI 0.12-0.63); rs3213255 adjHR 0.44 (95% CI 0.24-0.82)). The score for the number of variant alleles in the XRCC1 gene showed a trend of increasing survival, only among patients treated with chemotherapy (29% decrease of risk of death for each additional variant allele in XRCC1; 0% in patients treated otherwise). Functional studies performed in a group of healthy subjects showed that the XRCC1 SNP variants associated to survival in this study conferred lower DNA repair capacity. CONCLUSIONS: Patients with a higher number of genetic variants in the XRCC1 DNA repair gene, who received chemotherapy, had a significantly reduced risk of death. A proficient DNA repair can result in cellular resistance to therapy and in worse survival. This finding may have clinical implications.