title: Polymorphisms in the XRCC1 gene 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.
authors.affiliation: HuGeF Human Genetics Foundation, Torino, Italy. carlotta.sacerdote@cpo.it
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ricceri
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.forename: Silvia
authors.initials: S
authors.lastname: Polidoro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Allione
authors.forename: Rossana
authors.initials: R
authors.lastname: Critelli
authors.forename: Alessia
authors.initials: A
authors.lastname: Russo
authors.forename: Angeline S
authors.initials: AS
authors.lastname: Andrew
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Andrea
authors.initials: A
authors.lastname: Bosio
authors.forename: Giovanni
authors.initials: G
authors.lastname: Casetta
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cucchiarale
authors.forename: Paolo
authors.initials: P
authors.lastname: Destefanis
authors.forename: Paolo
authors.initials: P
authors.lastname: Gontero
authors.forename: Luigi
authors.initials: L
authors.lastname: Rolle
authors.forename: Andrea
authors.initials: A
authors.lastname: Zitella
authors.forename: Dario
authors.initials: D
authors.lastname: Fontana
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D013534:Survival; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human
keywords: DNA repair genes; XRCC1; bladder cancer; chemotherapy; survival
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