XPC single-nucleotide polymorphisms correlate with prolonged progression-free survival in advanced ovarian cancer

Abstract

Objective: The nucleotide excision repair (NER) pathway recruits more than 20 gene products to areas of DNA damage to repair and restore DNA integrity. This pathway plays a key role in response to platinum-induced DNA damage, the cornerstone of treatment for advanced epithelial ovarian cancer. Effective removal of bulky platinum DNA adducts allows cells to repair chemotherapy-induced damage and survive. Therefore, altered NER pathway activity can affect platinum responsiveness. We sought to determine whether single-nucleotide polymorphisms (SNPs) in the NER pathway could predict response to platinum-based chemotherapy in ovarian cancer. Under an institutional review board-approved protocol, we identified patients with advanced-stage, papillary serous ovarian cancers. All patients underwent primary cytoreductive surgery followed by platinum- based chemotherapy. Patients who received neoadjuvant chemotherapy or a non-platinum-based chemotherapeutic regimen were excluded. DNA was isolated from peripheral blood specimens. Sixteen SNPs within genes in the NER pathway (XPG, XPD, ERCC1, XPC, ERCC3, ERCC8, ERCC4, XPA, XPF) were genotyped by TaqMan PCR. Statistical analyses were performed with univariate and multivariate Cox proportional hazards regression analysis. Results:We identified 139 patientswith stage III and IV papillary serous ovarian cancer. Two SNPs in the XPC gene were significantly associated with prolonged progression-free survival (PFS). The presence of the minor allele in each XPC polymorphism predicted longer PFS. XPC (rs3731108) AG/GG versus AA was associated with a prolonged PFS of 21.3 months versus 13.4 months (HR=0.63, 95% CI=0.42-0.95, P=0.03). XPC (rs1124303) GT/TT versus GG was associated with a prolonged PFS of 22.8 months versus 14.9 months (HR=0.47, 95% CI=0.23-0.94, P=0.03). On multivariate analysis adjusting for BRCA status and optimal cytoreductive surgery, both XPC polymorphisms remained significantly associated with prolonged PFS. Conclusions: XPC is a key component of the nucleotide excision repair pathway that participates in DNA damage recognition and repair protein complex formation. Single-nucleotide polymorphisms in the XPC gene may represent a novel predictor of ovarian cancer response to platinum-based chemotherapy.