Interferon regulatory factor 1 is an independent predictor of platinum resistance and survival in high-grade serous ovarian carcinoma

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). Conclusion. 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. (C) 2014 Elsevier Inc. All rights reserved.