Polymorphisms in theXRCC1gene modify survival of bladder cancer patients treated with chemotherapy

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.

Differential response of normal and malignant urothelial cells to CHK1 and ATM inhibitors

“…Genetic variation in TP63C/T, TERTC/T, and SLC14A1C/T were also confirmed associated to bladder tumour in European and White population. Multiple SNPs in base excision repair system including XRCC1 modulate the risk of bladder cancer, which modify survival of bladder cancer patients treated with chemotherapy (Sacerdote et al, 2013;Xie et al, 2013). However, individual prediction of disease outcome based on "molecular markers" of bladder cancer is currently not reliable.…”

Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer

“…La Citt a della Salute e della Scienza, formerly S. Giovanni Battista hospital, in Turin, and were recruited during the years 1994 to 2008 (12,13). In total, 726 patients were recruited, followed up, and included in a survival analysis to investigate the effect on clinical outcome of patients' characteristics.…”

“…DNA was extracted from peripheral blood leukocytes as reported by Sacerdote and colleagues (13). The total amount of telomeric DNA was measured by quantitative real-time PCR as previously described by Zee and colleagues (14).…”

Association between polymorphisms in DNA repair gene <em>XRCC1</em> and non-melanoma skin cancer risk: a meta-analysis

“…Figl et al showed that variants in potential regulatory regions of DNA repair genes might influence disease outcome in melanoma patients and have potentially significant implications for patient surveillance and tailored treatment 63. XRCC1 risk allele may result in resistance to therapy and shorter survival in bladder cancer patients treated with chemotherapy 64. XRCC1 Gln allele genotype showed significant prognostic associations in hepatocellular carcinoma 65.…”