Feedback
Sample to Insight
Click here to learn more

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

Authors: Cohen SMosig RMoshier EPereira ERahaman JPrasad-Hayes MHalpert RBillaud JNDottino PMartignetti JA

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.

Fig. 1. IRF1 mechanistic network. IRF1-driven mechanistic network showing predicted activation status of the connected regulators.

Fig. 4. Survival analysis setting parameters included IRF1 (Affymetrix ID: 202531_at), as the gene of interest, and HGSOC. (A) Overall survival analysis in a platinum-only treatment group. Setting parameters also included surgical debulking with optimal or suboptimal outcome, platinum-based adjuvant chemotherapy, and no limit to the follow-up threshold. Therewas a significant difference in OS between low and high IRF1 expression groups (P= 0.0043). (B) Overall survival analysis in patients with optimal surgical debulking. Setting parameters also included surgical debulking with optimal outcome, platinum-based adjuvant chemotherapy, and no limit to the follow-up threshold. There was a significant difference in OS between low and high IRF1 expression groups (P= 0.025). (C) Overall survival analysis in patients with suboptimal debulking. Setting parameters also included surgical debulking with suboptimal outcome, platinum-based adjuvant chemotherapy, and no limit to the follow-up threshold. There was a significant difference in OS between lowand high IRF1 expression groups; (P= 0.041). (D) Elevated IRF1 expression is a strong predictor of overall survival across all stages and grades of ovarian cancer regardless of debulking status.

table1

Supplemental Table 1: Top 10 transcriptions regulators predicted to be activated.

Citation information: Cohen S, Mosig R, Moshier E, Pereira E, Rahaman J, Prasad-Hayes M, Halpert R, Billaud JN, Dottino P, Martignetti JA. PMID: 24995581