title: Genetic variability of DNA repair mechanisms and glutathione-S-transferase genes influences treatment outcome in osteosarcoma.
abstract: BACKGROUND
  Osteosarcoma patients are commonly treated with cisplatin-based preoperative and postoperative chemotherapy. Cisplatin binds to DNA and forms both intrastrand and interstrand crosslinks, inhibiting DNA replication. Glutathione-S-transferases (GSTs) participate in cisplatin detoxification, while several independent DNA repair mechanisms repair cisplatin-induced lesions. The aim of our study was to investigate the influence of genetic variability of DNA repair mechanisms and GSTs on efficacy and toxicity of cisplatin-based chemotherapy in osteosarcoma patients.
  
  
  METHODS
  A total of 66 osteosarcoma patients were genotyped for ERCC1, ERCC2, NBN, RAD51, XRCC3, and GSTP1 polymorphisms, as well as GSTM1 and GSTT1 gene deletion. We determined the influence of polymorphisms on survival and treatment outcome using Cox regression and logistic regression.
  
  
  RESULTS
  Carriers of at least one polymorphic ERCC2 rs1799793 allele had longer event-free survival (EFS) (P=0.006; hazard ratio (HR)=0.28; 95% confidence interval (CI)=0.11-0.70). Polymorphic GSTP1 rs1138272 allele was associated with both shorter EFS and OS (P=0.005; HR=3.67; 95%CI=1.47-9.16; and P=0.004; HR=3.52; 95%CI=1.51-8.22, respectively). Compared to the reference NBN CAA haplotype, NBN CGA haplotype was associated with shorter EFS (P=0.001; HR=4.12; 95%CI=1.77-9.56).
  
  
  CONCLUSIONS
  Our results suggest that DNA repair polymorphisms and GST polymorphisms could be used as predictive factors for cisplatin-based chemotherapy in osteosarcoma patients and could contribute to treatment personalization.
authors.affiliation: Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia. Electronic address: katja.goricar@mf.uni-lj.si.
authors.forename: Katja
authors.initials: K
authors.lastname: Goričar
authors.affiliation: Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. Electronic address: vkovac@onko-i.si.
authors.forename: Viljem
authors.initials: V
authors.lastname: Kovač
authors.affiliation: Oncology and Haematology Unit, University Children's Hospital, University Medical Centre, Bohoričeva 20, 1000 Ljubljana, Slovenia. Electronic address: janez.jazbec@mf.uni-lj.si.
authors.forename: Janez
authors.initials: J
authors.lastname: Jazbec
authors.affiliation: Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. Electronic address: bzakotnik@onko-i.si.
authors.forename: Branko
authors.initials: B
authors.lastname: Zakotnik
authors.affiliation: Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. Electronic address: jlamovec@onko-i.si.
authors.forename: Janez
authors.initials: J
authors.lastname: Lamovec
authors.affiliation: Pharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia. Electronic address: vita.dolzan@mf.uni-lj.si.
authors.forename: Vita
authors.initials: V
authors.lastname: Dolžan
mesh_terms: D000293:Adolescent; D000328:Adult; D002945:Cisplatin / Q000008:administration & dosage; D004260:DNA Repair; D005260:Female; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000235:genetics*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D005982:Glutathione Transferase; D002945:Cisplatin
keywords: Cisplatin; DNA repair; Osteosarcoma; Polymorphism