Abstract 5593: Transcriptome and pathway analysis identifies IRF1 as a predictor of progression free and overall survival in ovarian carcinoma

Abstract

Abstract Background: Epithelial Ovarian Cancer (EOC) is the most lethal female reproductive tract malignancy with nearly 200,000 new cases and > 125,000 deaths attributable to the disease each year worldwide. Most patients present with advanced stage disease and the cornerstone of treatment is surgical debulking followed by platinum-based chemotherapy. The major contributor to the high fatality-to-case ratio is chemoresistant disease. In fact, while 80% of patients have a complete clinical response to their primary therapy, the majority will die from disease recurrence within 5 years. The underlying tumor biology that distinguishes between platinum sensitivity and resistance is largely unknown. We sought to identify candidate biomarkers/pathways which could distinguish between these two states and test their prognostic ability. Methods: Ovarian tumor samples from patients with primary high-grade serous ovarian cancer were divided into two groups based on response to platinum status. Transcriptome analysis was performed using RNA-Seq and Ingenuity Pathway Analysis (IPA) was used to explore differences between these two sets of samples. Findings were validated using qtRT-PCR. Survival analysis was performed in two independent sample sets. The largest set consisted of the gene expression data and relapse free and overall survival information downloaded from GEO (Affymetrix microarrays only), EGA and TCGA, representing more than 1400 samples. Results: IPA highlighted that Interferon regulatory factor 1 (IRF1) was differentially expressed between the two clinical groups and that IRF1 expression was upregulated in the platinum-sensitive group. Validation studies performed on 31 patient tumor samples demonstrated a significant difference in PFS between the low and high IRF1 groups (P = 0.027) as well as a distinct difference in the probability of recurrence. High levels of IRF1 strongly correlated with increased overall survival in late-stage disease regardless of debulking status and grade in those patients who received platinum therapy. Conclusion: The goal of this study was to identify candidate genes/pathways which might play a role in distinguishing between different platinum states of EOC. Using an RNA-Seq / pathway based approach, we identified differential levels of IRF1 as a predictor of both PFS and OS in patients treated with platinum agents - the gold standard of treatment. Future studies will evaluate the clinical utility of these findings. Citation Format: John A. Martignetti, Samantha Cohen, Rebecca Mosig, Richard Halpert, Jean-Noel Billaud, Peter Dottino. Transcriptome and pathway analysis identifies IRF1 as a predictor of progression free and overall survival in ovarian carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5593. doi:10.1158/1538-7445.AM2014-5593