Katja Goričar1, Viljem Kovač2, Janez Jazbec3, Branko Zakotnik4, Janez Lamovec5, Vita Dolžan6. 1. 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. 2. Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. Electronic address: vkovac@onko-i.si. 3. Oncology and Haematology Unit, University Children's Hospital, University Medical Centre, Bohoričeva 20, 1000 Ljubljana, Slovenia. Electronic address: janez.jazbec@mf.uni-lj.si. 4. Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. Electronic address: bzakotnik@onko-i.si. 5. Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia. Electronic address: jlamovec@onko-i.si. 6. 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.
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.
BACKGROUND:Osteosarcomapatients 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 osteosarcomapatients. METHODS: A total of 66 osteosarcomapatients 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 ERCC2rs1799793 allele had longer event-free survival (EFS) (P=0.006; hazard ratio (HR)=0.28; 95% confidence interval (CI)=0.11-0.70). Polymorphic GSTP1rs1138272 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 osteosarcomapatients and could contribute to treatment personalization.
Authors: Emilyn Banfield; Austin L Brown; Erin C Peckham; Surya P Rednam; Jeffrey Murray; M Fatih Okcu; Laura E Mitchell; Murali M Chintagumpala; Ching C Lau; Michael E Scheurer; Philip J Lupo Journal: Cancer Epidemiol Date: 2016-09-05 Impact factor: 2.984
Authors: Srikanth R Ambati; Jae-Hung Shieh; Benet Pera; Eloisi Caldas Lopes; Anisha Chaudhry; Elissa W P Wong; Ashish Saxena; Tsann-Long Su; Malcolm A S Moore Journal: Oncotarget Date: 2016-07-12