Abstract
BackgroundPrimary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy. Platinum resistant cancers progress/recur in approximately 25% of cases within six months. We aimed to identify clinically useful biomarkers of platinum resistance.MethodsA database of ovarian cancer transcriptomic datasets including treatment and response information was set up by mining the GEO and TCGA repositories. Receiver operator characteristics (ROC) analysis was performed in R for each gene and these were then ranked using their achieved area under the curve (AUC) values. The most significant candidates were selected and in vitro functionally evaluated in four epithelial ovarian cancer cell lines (SKOV-3-, CAOV-3, ES-2 and OVCAR-3), using gene silencing combined with drug treatment in viability and apoptosis assays. We collected 94 tumor samples and the strongest candidate was validated by IHC and qRT-PCR in these.ResultsAll together 1,452 eligible patients were identified. Based on the ROC analysis the eight most significant genes were JRK, CNOT8, RTF1, CCT3, NFAT2CIP, MEK1, FUBP1 and CSDE1. Silencing of MEK1, CSDE1, CNOT8 and RTF1, and pharmacological inhibition of MEK1 caused significant sensitization in the cell lines. Of the eight genes, JRK (p = 3.2E-05), MEK1 (p = 0.0078), FUBP1 (p = 0.014) and CNOT8 (p = 0.00022) also correlated to progression free survival. The correlation between the best biomarker candidate MEK1 and survival was validated in two independent cohorts by qRT-PCR (n = 34, HR = 5.8, p = 0.003) and IHC (n = 59, HR = 4.3, p = 0.033).ConclusionWe identified MEK1 as a promising prognostic biomarker candidate correlated to response to platinum based chemotherapy in ovarian cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-837) contains supplementary material, which is available to authorized users.
Highlights
Primary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy
Database construction We identified 1,452 patients in 8 datasets meeting our criteria in GEO and TCGA
Receiver operator characteristics (ROC) analysis was performed for all genes, and the eight genes showing the highest area under the curve (AUC) value and highest significance were selected for further experiments
Summary
Primary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy. Platinum resistant cancers progress/recur in approximately 25% of cases within six months. We aimed to identify clinically useful biomarkers of platinum resistance. Ovarian cancer is the fifth leading cause of cancer death among women in the USA, with approximately 22,000 new cases and 14,000 deaths per year [1]. Primary treatment includes surgery and platinum-based chemotherapy. The platinum-taxane chemotherapy still represents the gold standard of treatment. Platinum agents bind DNA forming inter- and intrastrand DNA adducts [6]. Cellular perception of these DNA adducts leads to the activation of DNA-damage mediated apoptotic pathways. Resistance against carboplatin can evolve by three principal mechanisms: reduction of intracellular drug concentration (involving alterations in CTR1, CTR2, ATP7B, GST), changes in DNA repair (ERCC1, MLH1, MSH2, BRCA1/2) or modification of cellular response (TP53, ERBB2, CCNE) which mechanisms have been discussed previously [7,8]
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