Deolinda Pereira1,2, Joana Assis3,4, Mónica Gomes2,3,5, Augusto Nogueira3,4,5, Rui Medeiros6,7,8,9. 1. Oncology Department, Portuguese Institute of Oncology, Porto, Portugal. 2. ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal. 3. Molecular Oncology and Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. 4. FMUP, Faculty of Medicine, Porto University, Porto, Portugal. 5. Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal. 6. ICBAS, Abel Salazar Institute for the Biomedical Sciences, Porto, Portugal. ruimedei@ipoporto.min-saude.pt. 7. Molecular Oncology and Viral Pathology Group-Research Center, Portuguese Institute of Oncology, Edifício Laboratórios. 4° piso, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. ruimedei@ipoporto.min-saude.pt. 8. Research Department, Portuguese League Against Cancer (NRNorte), Porto, Portugal. ruimedei@ipoporto.min-saude.pt. 9. CEBIMED, Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal. ruimedei@ipoporto.min-saude.pt.
Abstract
PURPOSE: The success of chemotherapy in ovarian cancer (OC) is directly associated with the broad variability in platinum response, with implications in patients survival. This heterogeneous response might result from inter-individual variations in the platinum-detoxification pathway due to the expression of glutathione-S-transferase (GST) enzymes. We hypothesized that GSTM1 and GSTT1 polymorphisms might have an impact as prognostic and predictive determinants for OC. METHODS: We conducted a hospital-based study in a cohort of OC patients submitted to platinum-based chemotherapy. GSTM1 and GSTT1 genotypes were determined by multiplex PCR. RESULTS: GSTM1-null genotype patients presented a significantly longer 5-year survival and an improved time to progression when compared with GSTM1-wt genotype patients (log-rank test, P = 0.001 and P = 0.013, respectively). Multivariate Cox regression analysis indicates that the inclusion of genetic information regarding GSTM1 polymorphism increased the predictive ability of risk of death after OC platinum-based chemotherapy (c-index from 0.712 to 0.833). Namely, residual disease (HR, 4.90; P = 0.016) and GSTM1-wt genotype emerged as more important predictors of risk of death (HR, 2.29; P = 0.039; P = 0.036 after bootstrap). No similar effect on survival was observed regarding GSTT1 polymorphism, and there were no statistically significant differences between GSTM1 and GSTT1 genotypes and the assessed patients' clinical-pathological characteristics. CONCLUSION: GSTM1 polymorphism seems to have an impact in OC prognosis as it predicts a better response to platinum-based chemotherapy and hence an improved survival. The characterization of the GSTM1 genetic profile might be a useful molecular tool and a putative genetic marker for OC clinical outcome.
PURPOSE: The success of chemotherapy in ovarian cancer (OC) is directly associated with the broad variability in platinum response, with implications in patients survival. This heterogeneous response might result from inter-individual variations in the platinum-detoxification pathway due to the expression of glutathione-S-transferase (GST) enzymes. We hypothesized that GSTM1 and GSTT1 polymorphisms might have an impact as prognostic and predictive determinants for OC. METHODS: We conducted a hospital-based study in a cohort of OC patients submitted to platinum-based chemotherapy. GSTM1 and GSTT1 genotypes were determined by multiplex PCR. RESULTS:GSTM1-null genotype patients presented a significantly longer 5-year survival and an improved time to progression when compared with GSTM1-wt genotype patients (log-rank test, P = 0.001 and P = 0.013, respectively). Multivariate Cox regression analysis indicates that the inclusion of genetic information regarding GSTM1 polymorphism increased the predictive ability of risk of death after OC platinum-based chemotherapy (c-index from 0.712 to 0.833). Namely, residual disease (HR, 4.90; P = 0.016) and GSTM1-wt genotype emerged as more important predictors of risk of death (HR, 2.29; P = 0.039; P = 0.036 after bootstrap). No similar effect on survival was observed regarding GSTT1 polymorphism, and there were no statistically significant differences between GSTM1 and GSTT1 genotypes and the assessed patients' clinical-pathological characteristics. CONCLUSION:GSTM1 polymorphism seems to have an impact in OC prognosis as it predicts a better response to platinum-based chemotherapy and hence an improved survival. The characterization of the GSTM1 genetic profile might be a useful molecular tool and a putative genetic marker for OC clinical outcome.
Authors: S Pemble; K R Schroeder; S R Spencer; D J Meyer; E Hallier; H M Bolt; B Ketterer; J B Taylor Journal: Biochem J Date: 1994-05-15 Impact factor: 3.857
Authors: Jacques Ferlay; Isabelle Soerjomataram; Rajesh Dikshit; Sultan Eser; Colin Mathers; Marise Rebelo; Donald Maxwell Parkin; David Forman; Freddie Bray Journal: Int J Cancer Date: 2014-10-09 Impact factor: 7.396