Polymorphisms of DNA repair genes and treatment outcomes in advanced epithelial ovarian cancer
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Although platinum-based chemotherapy has been the cornerstone of treatment for ovarian cancer, drug resistance and severe toxicity remain great clinical challenges. Pharmacogenetic assessments of platinum agents have suggested that polymorphisms in DNA repair genes may be responsible for varying response to chemotherapy among individuals, affecting clinical outcome and toxicity. However, the data from ovarian cancer are limited. This study aimed to examine the relationships between common variations in DNA repair genes and treatment outcomes among advanced ovarian cancer patients after platinum-based chemotherapy. The study was conducted based on 385 patients who participated in the two GOG phase III clinical trials. All the patients were FIGO stage III optimally debulked and treated with cisplatin or carboplatin-based chemotherapy. With a candidate approach, 11 polymorphisms in eight leading DNA repair genes ( ERCC1 codon 118 and C8092A, XPD Lys751Gln and Asp312Asn, XPG Asp1104His, XPA G23A in nucleotide excision repair; XRCC1 Arg399Gln and Arg194Trp in base excision repair; XRCC3 Thr241, BRCA1 Pro871Leu, BRCA2 Asn372His in double-strand break repair) were selected for assessment. Genomic DNA was extracted from white blood cells and genotyping was carried out using pyrosequencing method or Sequonom's MALDI-TOF platform. The clinical endpoints were disease progression-free survival (PFS) and overall survival (OS). Leukopenia, thrombocytopenia, neutropenia, gastrointestinal toxicity and neurologic toxicity were also evaluated in relation to these polymorphisms. The hazard ratio (HR) of disease progression or death for heterozygous and homozygous variants compared to homozygous wild type was estimated using a Cox proportional hazards model. The odds ratio (OR) for occurring a toxicity was estimated using a Logistic regression model. The genetic polymorphisms at ERCC1 codon 118, C8092A and at BRCA1 Pro871Leu were found to predict clinical outcome. More specifically, CT or TT genotype at ERCC1 codon 118 was associated with a decreased risk of death compared to CC genotype (HR: 0.63, 95% CI: 0.47-0.86, P =0.003), but the risk reduction in the disease progression was not promised (HR: 0.85, 95% CI: 0.64-1.13, P =0.266); CA or AA genotype at ERCC1 C8092A was associated with an increased risk for disease progression (HR: 1.30, 95% CI: 1.04-1.64, P =0.022) or death (HR: 1.28, 95% CI: 1.00-1.65, P =0.054) compared to CC genotype; and CT or TT genotype at BRCA1 Pro871Leu also had an increased risk for disease progression (HR: 1.31, 95% CI: 1.03-1.67, P =0.026) or death (HR: 1.31, 95% CI: 1.00-1.71, P =0.047) compared to CC genotype. In addition, the polymorphism at XRCC1 Arg399Gln was associated with treatment adverse effect. An increased grade 3 or 4 leukopenia toxicity was observed among patients with this polymorphism (OR: 2.17, 95% CI: 1.38-3.41, P =0.0008 for GA+AA vs. GG genotype). There is no evidence that other polymorphisms were associated with either clinical outcome or toxicity. In conclusion, ERCC1 codon 118, C8092A and BRCA1 Pro871Leu polymorphisms may have the potential used for optimal chemotherapy among individuals with sporadic ovarian cancer. These findings provide evidence for future research.