title: DNA repair polymorphisms and treatment outcomes of patients with malignant mesothelioma treated with gemcitabine-platinum combination chemotherapy.
abstract: BACKGROUND
  Genetic polymorphisms that affect DNA repair capacity can modulate the efficacy and toxicity of cytotoxic agents. Therefore, the aim of our study was to evaluate the influence of genetic variability in DNA repair genes on treatment outcome in patients with malignant mesothelioma (MM) treated with gemcitabine-platinum combination chemotherapy.
  
  
  METHODS
  In total, 109 patients with MM were genotyped for 10 polymorphisms in XRCC1, NBN, RAD51, and XRCC3 genes. The influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity was determined by logistic regression analysis, whereas their influence on survival was estimated by Cox proportional hazards model.
  
  
  RESULTS
  There were no associations between the investigated polymorphisms and tumor response, but we observed a significant association between XRCC1 399Gln allele and reduced overall survival (hazards ratio = 1.70; 95% confidence interval [CI] 1.06-2.73; p = 0.028). Interaction between XRCC1 399Gln allele and C-reactive protein levels revealed that carriers of at least one XRCC1 399Gln allele with C-reactive protein levels above median had significantly shorter overall survival time compared with other patients (12.9 months versus 25.3 months, log-rank p < 0.001). We also observed an association between XRCC1 399Gln and lower frequency of leukopenia (odds ratio [OR] = 0.25; 95% CI 0.09-0.67; p = 0.006), neutropenia (OR = 0.24; 95% CI 0.09-0.68; p = 0.007), and thrombocytopenia (OR = 0.27; 95% CI 0.09-0.84; p = 0.024). In addition, NBN 3474A>C, XRCC3 -316A>G, and Thr241Met polymorphisms showed significant associations with treatment-related toxicity.
  
  
  CONCLUSIONS
  Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.
authors.affiliation: Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Nina
authors.initials: N
authors.lastname: Erčulj
authors.forename: Viljem
authors.initials: V
authors.lastname: Kovač
authors.forename: Julija
authors.initials: J
authors.lastname: Hmeljak
authors.forename: Alenka
authors.initials: A
authors.lastname: Franko
authors.forename: Metoda
authors.initials: M
authors.lastname: Dodič-Fikfak
authors.forename: Vita
authors.initials: V
authors.lastname: Dolžan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics; D004247:DNA / Q000032:analysis / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010984:Platinum / Q000008:administration & dosage; D016066:Pleural Effusion, Malignant / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D051135:Rad51 Recombinase / Q000235:genetics; D015996:Survival Rate; D000076105:X-ray Repair Cross Complementing Protein 1; D000093542:Gemcitabine
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C110901:X-ray repair cross complementing protein 3; C000619371:XRCC1 protein, human; D003841:Deoxycytidine; D010984:Platinum; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000093542:Gemcitabine