title: MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  A 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.
  
  
  RESULTS
  All 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).
  
  
  CONCLUSIONS
  We identified MEK1 as a promising prognostic biomarker candidate correlated to response to platinum based chemotherapy in ovarian cancer.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Pénzváltó
authors.forename: András
authors.initials: A
authors.lastname: Lánczky
authors.forename: Julianna
authors.initials: J
authors.lastname: Lénárt
authors.forename: Nóra
authors.initials: N
authors.lastname: Meggyesházi
authors.forename: Tibor
authors.initials: T
authors.lastname: Krenács
authors.forename: Norbert
authors.initials: N
authors.lastname: Szoboszlai
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.forename: Imre
authors.initials: I
authors.lastname: Pete
authors.affiliation: MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary. gyorffy.balazs@ttk.mta.hu.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D016190:Carboplatin / Q000494:pharmacology* / Q000627:therapeutic use; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015331:Cohort Studies; D019295:Computational Biology; D030561:Databases, Nucleic Acid; D066264:Datasets as Topic; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D016190:Carboplatin; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human