Genetic polymorphisms of GSTP1,XRCC1, XPC and ERCC1: prediction of clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer patients of Bangladesh

Abstract

Background: Lung cancer is the second leading cause of cancer related death worldwide as well as in Bangladesh. Platinum-based chemotherapy is considered as the first-line treatment for lung cancer. But non-small cell lung cancer (NSCLC) is relatively insensitive to chemotherapy compared to other type of lung cancer. Chemotherapy resistance and platinum-induced toxicities are major obstacle for successful chemotherapy in NSCLC patients. The goal of this study is to evaluate the role of genetic polymorphism of GSTP1 (rs1695), XRCC1 (rs25487), XPC (rs2228001) and ERCC1 (rs11615) genes to the response and toxicities produced by platinum based chemotherapy used in the treatment of non-small cell lung cancer. Methods: Two hundred and eighty five patients with non-small cell lung cancer were recruited from different public and private hospitals of Bangladesh who received platinum based chemotherapy. Each volunteer signed an informed consent document before entering the study. A measure of 3ml of venous blood was collected into a tube with EDTA-Na2 and stored at -800C. After extraction of genomic DNA, Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method was used to analyze the genetic polymorphisms of GSTP1, XRCC1, XPC and ERCC1 genes. Then amplified DNA fragments were digested with restriction enzymes and gel electrophoresis was carried out to identify the targeted alleles. The assessment of chemotherapy induced toxicities was done with the help of common terminology criteria for adverse events (CTCAEv4.0).CT scan was performed for one hundred and fifty patients before and after chemotherapy for the evaluation of response to treatment. The American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system (sixth edition) and Response Evaluation Criteria In Solid Tumors (RECIST) were used to evaluate the pathological response of primary tumor and axillary lymph nodes. Results: In our study, Patients carrying AG and AG+GG genotypes of GSTP1 polymorphism showed a significantly good response to platinum based chemotherapy than did those carrying AA genotype (p = 0.034 and p = 0.037 respectively). AG genotype and at least one variant A allele (AA + AG) of XRCC1 (rs25487) showed an elevated response to chemotherapy than did those carrying the GG genotype ( p = 0.027, p = 0.002). No significant association was found in case of XPC and ERCC1 polymorphisms with response to chemotherapy in our study. In the case of toxicity evaluation, patients carrying GG genotype of GSTP1 had higher risk for the development of neutropenia (p = 0.043) compared to those with AA genotype. The patients carrying AG genotype and at least one variant A (AA+AG) genotype of XRCC1 had an elevated risk for the development of anemia, neutropenia, thrombocytopenia and gastrointestinal toxicity (p<0.05) compared to those with GG genotype. Patients carrying AC genotype of XPC had significantly higher risk of neutropenia than did those carrying AA genotype ( p = 0.016). No significant relationship of ERCC1 polymorphism with any platinum induced toxicity and response was found in our study (p > 0.05).The response to the treatment as well as toxicity was not significantly associated with different demographic and clinicophathological characteristics in our study. Discussion:Our result indicates that GSTP1 polymorphism was strongly associated with the response of chemotherapy due to the reduced detoxification ability of patients carrying G allele. Furthermore, patients carrying GG genotype hadhigher risk for the development of neutropenia compared to those with AA genotype. This might be due to differential capacities of normal and malignant cells in dealing with drug cytotoxicity, which could be further attributed to somatic changes incurred during tumorigenesis in cancer cells. An elevated response was also found in case of XRCC1 due to increased DNA damage and chemotherapy sensitivity by G allele. The patients carrying AG genotype and at least one variant A genotype of XRCC1 had an elevated risk for the development of different type of toxicities. This might be due to increased DNA damage, reduced repairing capacity and chemotherapy sensitivity by G allele. Patients carrying AC genotype of XPC were found to be associated with neutropenia compared to those with AA genotype. This might be due to the potentially influence of the acute hematological toxicity in platinum based chemotherapy, owing to the decreased repair capacity of DNA damaged by platinum based drug in myelocytes. Conclusion:Although we have some limitations in this study and major one is that we selected only GSTP1 XRCC1, XPC and ERCC1, which account for the phase II metabolism, base excision repair and nuclear excision repair pathway, our findings, open some windows in further wide range of researches in the field of personalized medicine. Our study suggests that GSTP1, XRCC1 and XPC might affect the clini¬cal outcome of patients with advanced NSCLC receiving platinum-based chemotherapy. This observation could be used in personalized chemotherapy strategies to increase the response rate and prolonged survival time. On the basis of these findings, it may be possible to use these polymorphisms in the future as a biomarker to predict the outcomes of personalized platinum chemotherapy.