Abstract
The nucleotide excision repair (NER) and base excision repair (BER) pathways, two DNA repair pathways, are related to platinum resistance in cancer treatment. In this paper, we studied the association between single nucleotide polymorphisms (SNPs) of involved genes and response to platinum-based chemotherapy in epithelial ovarian cancer. Eight SNPs in XRCC1 (BER), XPC and XPD (NER) were assessed in 213 patients with epithelial ovarian cancer using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and primer-introduced restriction analysis-polymerase chain reaction (PIRA-PCR) techniques. The median progression-free survival (PFS) of patients carrying the Lys/Lys and Lys/Gln+Gln/Gln genotype of the XPC Lys/Gln polymorphism were 25 and 12 months, respectively (P=0.039); and the mean overall survival (OS) of patients was 31.1 and 27.8 months, respectively (P=0.048). Cox's multivariate analysis suggested that patients with epithelial ovarian cancer with the Gln allele had an increased risk of death (HR=1.75; 95% CI=1.06-2.91) compared to those with the Lys/Lys genotype. There are no associations between the XPC PAT+/-, XRCC1 Arg194Trp, Arg280His, Arg399Gln, and XPD Asp312Asn, Lys751Gln polymorphisms and the survival of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy. Our results indicated that the XPC Lys939Gln polymorphism may correlate with clinical outcome of patients with epithelial ovarian cancer when treated with platinum-based chemotherapy in Northern China.
Highlights
Within all gynecological malignancies, ovarian cancer is the leading cause of death in Chinese women (Cao, 2004)
Clinical cancer outcomes and responsiveness to platinum-based chemotherapy are attributable to some single nucleotide polymorphisms (SNPs) of the nucleotide excision repair (NER) and base excision repair (BER) pathway genes (Yu et al, 2008; Kalikali et al, 2009; Sun et al, 2009)
Previous studies showed that polymorphisms of Arg194Trp and Arg399Gln in the XRCC1 gene, PAT+/in the XPC gene, and Asp312Asn and Lys751Gln in the XPD gene were not associated with the response rate of epithelial ovarian cancer to platinum-based chemotherapy (Saldivar et al, 2007; Kim et al, 2009)
Summary
Ovarian cancer is the leading cause of death in Chinese women (Cao, 2004). Symptom-free stage of the disease, approximately two-thirds of patients will have developed peritoneal and lymph node metastasis. The overall 5-year survival rate of advanced ovarian cancer is roughly 20-25%. Cytoreductive surgery alone is an insufficient treatment, and the prognosis for the patient mainly depends on cancer responsiveness to subsequent chemotherapy. The standard first-line chemotherapy for advanced ovarian cancer is a combination of platinum with either cyclophosphamide or paclitaxel administered after surgery (du et al, 2004). 30% of patients do not respond to platinum-based chemotherapy in the first attempt. One of the mechanisms by which the tumor cells develop resistance to platinum agents is by the enhanced repair of bulky DNA adducts (Reed, 1998). DNA repair capacity (DRC) is an important determinant of the resistance to platinum agents. XRCC1 Arg194Trp (C/T) Exon 6 XRCC1 Arg280His (G/A) Exon 9 XRCC1 Arg399Gln (G/A) Exon 10 XPC Ala499Val (C/T) Exon 8 XPC PAT+/Intron 9 XPC Lys939Gln (A/C) Exon 15 XPD Asp312Asn (G/A) Exon 10 XPD Lys751Gln (A/C) Exon 23
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