Xeroderma pigmentosum complementation group C single-nucleotide polymorphisms in the nucleotide excision repair pathway correlate with prolonged progression-free survival in advanced ovarian cancer

Abstract

BACKGROUND: The nucleotide excision repair (NER) pathway is the principal DNA repair pathway for removing bulky platinum DNA adducts. Suboptimal DNA repair may lead to improved response to platinum agents. The objective of this study was to determine whether single-nucleotide polymorphisms (SNPs) in NER pathway genes could be markers of platinum response in ovarian cancer. METHODS: The authors identified patients with advanced-stage, papillary serous ovarian cancer who underwent primary cytoreductive surgery followed by platinum-based chemotherapy. DNA was isolated from peripheral blood specimens. Twenty-two SNPs within NER genes (xeroderma pigmentosum [XP] complementation group A [XPA], XPB/excision repair cross-complementing rodent repair deficiency, complementation group 3 [ERCC3], XPC, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5, Cockayne syndrome group B protein [CSB]/ERCC8, ERCC1) were genotyped using polymerase chain reaction analysis. RESULTS: In total, 139 patients with stage III and IV papillary serous ovarian cancer were genotyped. The XPC (reference SNP 3731108 [rs3731108]) adenosine-guanine (AG)/AA genotype versus the GG genotype was associated with prolonged a progression-free survival (PFS) of 21.3 months versus 13.4 months (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.42-0.95; P =.03). The XPC (rs1124303) guanosine-thymidine (GT)/GG genotype versus the TT genotype was associated with a prolonged PFS of 22.8 months versus 14.9 months (HR, 0.47; 95% CI, 0.24-0.94; P =.03). The XPC poly(AT) (PAT) (-/+)/(-/-) genotype versus the (+/+) genotype was associated with a prolonged PFS of 17 months versus 11.6 months (HR, 0.56; 95% CI, 0.36-0.89; P =.01). The XPF/ERCC4 (rs12926685) cytidine-thymidine (CT)/CC genotype versus the TT genotype was associated with a prolonged PFS of 16.7 months versus 12.4 months (HR, 0.63; 95% CI, 0.41-0.95; P =.03). On multivariate analysis adjusting for breast cancer (BRCA) gene and cytoreductive surgery status, the XPC SNPs remained significantly associated with prolonged PFS. CONCLUSIONS: The current results indicated that XPC is a key component of the NER pathway that participates in DNA damage repair. SNPs in the XPC gene may represent novel markers of ovarian cancer response to platinum-based chemotherapy. © 2011 American Cancer Society.