title: Interferon regulatory factor 1 is an independent predictor of platinum resistance and survival in high-grade serous ovarian carcinoma.
abstract: OBJECTIVE
  High-grade serous ovarian cancer (HGSOC) that is resistant to platinum-based chemotherapy has a particularly poor prognosis. Response to platinum has both prognostic survival value and dictates secondary treatment strategies. Using transcriptome analysis, we sought to identify differentially expressed genes/pathways based on a tumor's platinum response for discovering novel predictive biomarkers.
  
  
  METHODS
  Seven primary HGSOC tumor samples, representing two extremes of platinum sensitivity/timing of disease recurrence, were analyzed by RNA-Seq, Ingenuity Pathways Analysis (IPA) and Upstream Regulator Analysis (URA), and used to explore differentially expressed genes and prevalent molecular and cellular processes. Progression-free and overall survival (PFS, OS) was estimated using the Kaplan-Meier method in two different sample sets including GEO and TCGA data sets.
  
  
  RESULTS
  IPA and URA highlighted an IRF1-driven transcriptional program (P=0.0017; z-score of 3.091) in the platinum sensitive improved PFS group. QRT-PCR analysis of 31 HGSOC samples demonstrated a significant difference in PFS between low and high IRF1 expression groups (P=0.048) and between groups that were platinum sensitive versus not (P=0.016). In a larger validation data set, increased levels of IRF1 were associated with both increased PFS (P=0.043) and OS (P=0.019) and the effect on OS was independent of debulking status (optimal debulking, P=0.025; suboptimal, P=0.041).
  
  
  CONCLUSIONS
  Transcriptome analysis identifies IRF1, a transcription factor that functions both in immune regulation and as a tumor suppressor, as being associated with platinum sensitivity and an independent predictor of both PFS and OS in HGSOC.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mosig
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Moshier
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Pereira
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jamal
authors.initials: J
authors.lastname: Rahaman
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Prasad-Hayes
authors.affiliation: Qiagen, Redwood City, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Halpert
authors.affiliation: Qiagen, Redwood City, CA, USA.
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Billaud
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Dottino
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: john.martignetti@mssm.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Martignetti
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D002945:Cisplatin
keywords: Biomarker; Cisplatin-resistance; IRF1; Ovarian cancer; Survival