| Affiliation: | 1. HuGeF Human Genetics Foundation, , Torino, Italy;2. Unit of Cancer Epidemiology, University of Turin and Centre for Cancer Epidemiology and Prevention (CPO Piemonte), , Torino, Italy;3. Department of Genetics, Biology and Biochemistry, University of Torino, , Torino, Italy;4. Section of Biostatics and Epidemiology, Dartmouth Medical School, , Lebanon, NH;5. Department of Epidemiology, M.D. Anderson Cancer Center, , Houston, TX;6. Department of Epidemiology, Biostatistics & HTA, Radboud University Medical Centre, NL‐6500 HB, , Nijmegen, The Netherlands;7. Department of Urology, Radboud University Medical Centre, NL‐6500 HB, , Nijmegen, The Netherlands;8. Department of Urology 2, San Giovanni Battista Hospital and University of Torino, , Torino, Italy;9. Department of Urology 1, San Giovanni Battista Hospital and University of Torino, , Torino, Italy;10. Department of Urology, Clinica Cellini, , Torino, Italy;11. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, , London, United Kingdom |
| Abstract: | Survival of bladder cancer patients depends on several factors including disease stage and grade at diagnosis, age, health status of the patient and the applied treatment. Several studies investigated the role of DNA repair genetic variants in cancer susceptibility, but only few studies investigated their role in survival and response to chemotherapy for bladder cancer. We genotyped 28 single nucleotide polymorphisms (SNP) in DNA repair genes in 456 bladder cancer patients, reconstructed haplotypes and calculated a score for combinations of the SNPs. We estimated Hazard Ratios (adjHR) for time to death. Among patients treated with chemotherapy, variant alleles of five SNPs in the XRCC1 gene conferred better survival (rs915927 adjHR 0.55 (95%CI 0.32–0.94); rs76507 adjHR 0.48 (95%CI 0.27–0.84); rs2854501 adjHR 0.25 (95%CI 0.12–0.52); rs2854509 adjHR 0.21 (95%CI 0.09–0.46); rs3213255 adjHR 0.46 (95%CI 0.26–0.80). In this group of patients, an increasing number of variant alleles in a XRCC1 gene score were associated with a better survival (26% decrease of risk of death for each additional variant allele in XRCC1). By functional analyses we demonstrated that the previous XRCC1 SNPs confer lower DNA repair capacity. This may support the hypothesis that survival in these patients may be modulated by the different DNA repair capacity determined by genetic variants. Chemotherapy treated cancer patients bearing an increasing number of “risky” alleles in XRCC1 gene had a better survival, suggesting that a proficient DNA repair may result in resistance to therapy and shorter survival. This finding may have clinical implications for the choice of therapy. |
