title: The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma.
abstract: BACKGROUND
  Platinum-based therapy is widely used in the treatment of malignant mesothelioma (MM); however, the efficacy and toxicity of platinum agents vary greatly between patients. The aim of our study was to evaluate the influence of platinum pathway polymorphisms on treatment outcome in patients with MM.
  
  
  METHODS
  In total, 133 patients with MM treated with (n = 97) or without (n = 36) platinum-based therapy were genotyped for common XPD, ERCC1, and GSTP1 polymorphisms, as well as for GSTM1 and GSTT1 gene deletion. Haplotype analysis was carried out to assess the combined effect of nucleotide excision repair (NER) polymorphisms.
  
  
  RESULTS
  GST polymorphisms were not associated with treatment outcome in patients with MM. In the group of platinum-treated patients with MM, ERCC1 8092C/C wild-type genotype significantly influenced progression-free survival (PFS) in multivariable analysis accounting for clinical variables (P = 0.034). XPD 312Asp/Asp and ERCC1 8092C/C wild-type genotypes also increased the odds of treatment-related toxic effects in univariable as well as multivariable analysis. The association of wild-type NER genotypes with better PFS and higher susceptibility to treatment-related toxic effects was confirmed in haplotype analysis.
  
  
  CONCLUSIONS
  Our results suggest that polymorphisms in NER pathway influence platinum-treatment efficacy and toxicity; therefore, these should be further evaluated as potential markers for the prediction of clinical outcome in patients with MM.
authors.affiliation: Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: N
authors.initials: N
authors.lastname: Erčulj
authors.forename: V
authors.initials: V
authors.lastname: Kovač
authors.forename: J
authors.initials: J
authors.lastname: Hmeljak
authors.forename: V
authors.initials: V
authors.lastname: Dolžan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000505:Alopecia / Q000139:chemically induced / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002945:Cisplatin / Q000008:administration & dosage; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D004720:Endonucleases / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005982:Glutathione Transferase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000235:genetics; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D017422:Sequence Analysis, DNA; D013921:Thrombocytopenia / Q000139:chemically induced / Q000235:genetics; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D016190:Carboplatin; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D002945:Cisplatin