ERCC5 Is a Novel Biomarker of Ovarian Cancer Prognosis

Department of Obstetrics and Gynecology, Cedars-Sinai Women's Cancer Research Institute, Samuel Oschin Comprehensive Cancer Institute, David Geffen School of Medicine, University of California at Los Angeles, CA 90048, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2008; 26(18):2952-8. DOI: 10.1200/JCO.2007.13.5806
Source: PubMed


To identify a biomarker of ovarian cancer response to chemotherapy. PATIENTS AND METHODS Study: participants had epithelial ovarian cancer treated with surgery followed by platinum-based chemotherapy. DNA and RNA were isolated from frozen tumors and normal DNA was isolated from matched peripheral blood. A whole-genome loss of heterozygosity (LOH) analysis was performed using a high-density oligonucleotide array. Candidate genomic areas that predicted enhanced response to chemotherapy were identified with Cox proportional hazards methods. Gene expression analyses were performed through microarray experiments. Candidate genes were tested for independent effects on survival using Cox proportional hazards models, Kaplan-Meier survival curves, and the log-rank test.
Using a whole-genome approach to study the molecular determinants of ovarian cancer response to platinum-based chemotherapy, we identified LOH of a 13q region to predict prolonged progression-free survival (PFS; hazard ratio, 0.23; P = .006). ERCC5 was identified as a candidate gene in this region because of its known function in the nucleotide excision repair pathway, the unique DNA repair pathway that removes platinum-DNA adducts. We found LOH of the ERCC5 gene locus and downregulation of ERCC5 gene expression to predict prolonged PFS. Integration of genomic and gene expression data shows a correlation between 13q LOH and ERCC5 gene downregulation.
ERCC5 is a novel biomarker of ovarian cancer prognosis and a potential therapeutic target of ovarian cancer response to platinum chemotherapy.

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    • "Previous studies showed enhanced NER activity to the resistance of platinum agents and diminished NER activity to the sensitivity of platinum agents. Previous studies have indicated XPG may have a role on the response to chemotherapy in various cancers, such as colorectal cancer, lung cancer and ovarian cancer (Walsh et al., 2008; Chen et al., 2009; Liu et al., 2012). A previous study has shown that those carrying XPG rs1047768TT are more likely to have poor responder than CC genotype (Liu et al., 2012). "
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    ABSTRACT: Polymorphisms in XPG are considered to contribute to the clinical outcome of patients receiving platinum drug chemotherapy. We aimed to investigate the role of five potential SNPs of XPG gene on the response to platinum-based chemotherapy in advanced Chinese NSCLC patients. A total of 451 patients with newly diagnosed and histopathologically confirmed primary NSCLC were consecutively collected. XPG rs2296147, rs4150261, rs17655, rs1047768 and rs2094258 were genotyped by the Taqman real-time polymerase chain reaction (PCR). In our study, we found patients carrying rs1057768 TT genotype had a significantly lower treatment response when compared with the CC genotype (OR=0.38, 95% CI=0.18-0.78). Patients carrying rs1047768 TT genotype showed a significantly short median PFS (11.2 months) and OS (13.6 months) than CC genotype, and the hazard ratios (HR) for PFS and OS were 2.06 (1.01-4.50) and 2.29 (1.21-2.49), respectively. Moreover, we found a significant decreased risk of death from NSCLC among patients carrying the rs2296147 TT genotype when compared with the CC genotype, the HR (95% CI) for OS being 0.50 (0.27-0.95). In conclusion, our study found that polymorphisms in rs1047768 C/T and rs2296147 C/T are associated with response to platinum-based chemotherapy in advanced NSCLC, and XPG polymorphisms could be predictive of prognosis.
    Preview · Article · Feb 2013 · Asian Pacific journal of cancer prevention: APJCP
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    • "such as double-strand breaks, through a nonhomologous end-joining pathway (Lindahl et al., 1999;Weaver et al., 2005). In vitro and in vivo studies have demonstrated that those genes in the NER and BER pathway are involved in the pharmacokinetics of platinum-based drugs and platinum resistance of cancer patients (Rosell et al., 2003; Azuma et al., 2007; Walsh et al., 2008). Single nucleotide polymorphisms (SNPs) in any of the NER and BER genes may modulate DRC and contribute to individual variations in chemotherapy response (Yu et al., 2008; Kalikali et al., 2009; Sun et al., 2009; Fleming et al., 2012). "
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    ABSTRACT: Objective: 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. Method: 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. Results: 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. Conclusion: 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.
    Preview · Article · Feb 2013 · Asian Pacific journal of cancer prevention: APJCP
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    • "This heterogeneous outcome suggests the existence of biologically different forms. Potential prognostic or predictive biomarkers, such as TP53, MYC, ABC transporters, BCL2, or BRCA genes (Williams et al, 2005; Kommoss et al, 2007; Walsh et al, 2008; Gadducci et al, 2009), have been identified. However, none has been validated for routine use. "
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    ABSTRACT: Prognosis of ovarian carcinoma is poor, heterogeneous, and not accurately predicted by histoclinical features. We analysed gene expression profiles of ovarian carcinomas to identify a multigene expression model associated with survival after platinum-based therapy. Data from 401 ovarian carcinoma samples were analysed. The learning set included 35 cases profiled using whole-genome DNA chips. The validation set included 366 cases from five independent public data sets. Whole-genome unsupervised analysis could not distinguish poor from good prognosis samples. By supervised analysis, we built a seven-gene optimal prognostic model (OPM) out of 94 genes identified as associated with progression-free survival. Using the OPM, we could classify patients in two groups with different overall survival (OS) not only in the learning set, but also in the validation set. Five-year OS was 57 and 27% for the predicted 'Favourable' and 'Unfavourable' classes, respectively. In multivariate analysis, the OPM outperformed the individual current prognostic factors, both in the learning and the validation sets, and added independent prognostic information. We defined a seven-gene model associated with outcome in 401 ovarian carcinomas. Prospective studies are warranted to confirm its prognostic value, and explore its potential ability for better tailoring systemic therapies in advanced-stage tumours.
    Full-text · Article · Jun 2011 · British Journal of Cancer
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