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 theinfluence of platinum pathway polymorphisms on treatment outcome in patients with MM. Patients and Methods: In total, 133 patients with MM treatedwith (n = 97) or without (n = 36) platinum-based therapy were genotypedfor 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-typegenotype 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 NERpathway 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.
F.02 Acquisition of new scientific knowledge
COBISS.SI-ID: 28755417Documented by almost five hundred references on 65 pages, the chapter provides a systematic overview of enzymes involved in Phase 1 of drug and xenobiotic metabolism (activation) and their corressponding genes. It describes their role in the metabolism of drugs and other xenobiotics as well as in the metabolism of the endogenous substrates. The chapter also summarizes the current knowledge of the importance of genetic polymorphisms of Phase 1 enzymes, especially cytochromes P450 in clinical practice. The chapter on pharmacogenetics of enzymes involved in Phase 1 of metabolism of drugs and xenobiotics is a part of the book "Pharmacogenetics and Individualized Medicine" which was published by John Wiley & Sons in 2012 and presents the current knowledge in the field of pharmacogenetics and comprehensivly covers the metabolism of drugs and xenobiotics, the influence of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of the active substances and the importance of pharmacogenetics for specific clinical areas. It also summarizes the developments in the field of new technological approaches in pharmacogenetics and highlights the problems associated with the transfer into clinical practice and the development of new drugs. The book was edited by Anke-Hilse Maitland-van der Zee from the University of Utrecht and Ann K. Daly from the University of Newcastle.
F.30 Professional assessment of the situation
COBISS.SI-ID: 30003673Background: The genetic factors may modify the individual susceptibility to the development of asbestosis. This study investigated whether MnSOD, ECSOD, CAT, iNOS, GSTM1, GSTT1 and GSTP1 genetic polymorphisms represent risk factors for asbestosis in workers occupationally exposed to asbestos. Methods: The nested case-control study included 262 cases with asbestosis and 265 controls with no asbestos-related disease. Data on cumulative asbestos exposure and smoking were available for all subjects. PCR based methods were used to genotype MnSOD Ala –9Val, ECSOD Arg213Gly, CAT –262C)T, iNOS (CCTTT)n, GSTM1-null, GSTT1-null, GSTP1 Ile105Val and Ala114Val polymorphisms. To assess asbestosis risk, logistic regression analysis was used. Results: The key findings of this study were that the GSTP1 coding for an enzyme with high conjugation capacity and the MnSOD -9Ala/Ala significantly increase the risk of developing asbestosis, whereas a protective effect was found for the GSTT1-null genotype. This study also demonstrated a strong interaction between MnSOD Ala –9Val and CAT –262C)T polymorphisms as well as between iNOS CCTTT and CAT –262C)T polymorphisms. Important findings of the current study show that the association between smoking and asbestosis is modified by GSTM1-null and iNOS CCTTT polymorphisms. Additional studies are needed to clarify whether MnSOD, ECSOD, CAT, and iNOS genotypes confound or modify the cumulative asbestos exposure – asbestosis associations. Conclusions: The findings of the current study suggest that, in addition to asbestos exposure, the genetic factors involved in the defense against ROS may also have an important influence on the development of asbestosis and should be seriously considered in future research on occupational/environmental asbestos-related diseases.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 30504665Asbestosis is among the most frequent diseases caused by asbestos. Although the causal relationship between asbestos exposure and asbestosis has been well proved, Iittle is known about the genetic factors that may influence the development of this disease. The aim of our study that we present as an example of gene-environment interactions is to investigate whether GSTM1, GSTT1, GSTP1, MnSOD, ECSOD, CA T and iNOS genetic polymorphisms represent risk factors for the development of asbestosis in workers occupationally exposed to asbestos and to study the possible interactions between genetic factors and environmental factors (asbestos exposure and smoking). The study included 262 patients with asbestosis and 265 workers from the same environment who did not develop any asbestos-related disease. Data on cumulative asbestos exposure and smoking were available for the entire study population. PCR based methods were used to genotype GSTM1-null, GSTT1- nu1l, GSTP1 lIe105Val and Ala114Val, MnSOD Ala -9Val, ECSOD Arg213Gly, CAT -262C)T and iNOS (CCTTT)n polymorphisms. Logistic regression analysis was used to assess the association between asbestosis and different variables. Asbestosis was associated with the logarithm of cumulative asbestos exposure (OR = 3.21, 95% CI = 2.43-4.23), whereas no association was found for smoking (OR = 0.98, 95% CI = 0.69-1.39). The OR of asbestosis was 1.01 (95% CI = 0.71-1.43) for the GSTM1-null genotype; 0.61 (95% CI 0.40-0.94) for the GSTT1-null genotype; 1.49 (95% CI = 1.06-2.10) for the GSTP1 genotype coding for an enzyme with high conjugation capacity versus genotypes resulting in intermediate or low enzyme activity; 1.50 (95% CI = 1.01-2.24) for the MnSOD -9Ala/Ala genotype versus the combined AlaNal and ValNal genotypes; 1.63 (95% CI = 0.62-4.27) for the ECSOD 213Arg/Gly genotype compared to the Arg/Arg genotype; (Abstract truncated at 2000 characters)
B.04 Guest lecture
COBISS.SI-ID: 30501593Cancer treatment is associated with a great heterogeneity in patient response. This hampers the early prediction of tumor response and/or drug toxicity that is particularly important for planning and individualization of chemotherapy in cancers with poor prognosis such as malignant mesothelioma (MM). Systemic treatment with cytotoxic agents remains the standard treatment option for the majority of MM patients and improves survival, clinical response and quality of life. Comparable response rates are achieved by combination of cisplatin with gemcitabine or with pemetrexed. The therapy is mainly guided by tumor biology and patients characteristics such as age and performance status, although many studies have searched for potential diagnostic and prognostic biomarkers in MM. We have determined the differences in SMRP levels in patients with MM before treatment and in various responses to treatment. Our findings suggested that SMRP may be a useful tumor marker for detecting the progression of MM and evaluating tumor response to treatment. We have also identified novel pharmacogenetic markers that would allow the prediction of MM patients that may respond to combination treatment with gemcitabine and cisplatin and patients at risk for no response or even disease progression on one hand or increased toxicity on the other hand. Our results indicated that genetic variability in candidate genes coding for enzymes involved in gemcitabine pathway, cisplatin disposition and DNA repair significantly influence treatment response in MM. Genotyping for these polymorphisms prior to chemotherapy would allow an early choice of the treatment protocol that may result in better treatment response and improved outcome and survival in a particular patient.
B.03 Paper at an international scientific conference
COBISS.SI-ID: 1509755