Transcriptome Analysis of Matched Cohorts of Long- and Short-term Survivors in Advanced High-Grade Serous Tubo-ovarian Cancer

Abstract

Objective: The late-stage diagnosis and the aggressiveness of high-grade serous tubo-ovarian carcinoma (HGSC) often results in poor survival outcomes, yet some patients exhibit an exceptionally long survival rate.This study aimed to identify molecular profiles associated with long-term/short-term survival in HGSC, with the goal of better understanding protective factors and developing new treatments. Experimental Design: To discover molecular drivers causing aggressiveness of HGSC, tumor samples from 12 long-term HGSC survivors (> 7 years overall survival) and 12 short-term survivors (< 1 year overall survival) were analyzed using targeted RNA sequencing followed by computational analysis. We investigated differentially expressed genes and their functional relevance, inferred differences in cell-type composition and signaling pathways as well as mutation status. To validate our findings, we simulated our study design by using HGSC TCGA dataset samples. We evaluated differential patterns of gene expression between these two groups and developed molecular profiles of HGSC that correlate with survival phenotypes. Results: Besides known molecular cancer drivers and indicators of poor prognosis, we identified specific transcriptional changes between short-term and long-term survivors of HGSC which indicate that immune processes play a fundamental role in long-term survivors. Our computational analysis reveals an important role of the ensemble of IFN-γ signaling and the RFX transcription factors as well as the immune cell composition of the tumor microenvironment. Conclusion: Specific immunologic requirements involving IFN-γ signaling and affected pathways seem to be relevant for long term survival in the generally considered non-immunogenic HGSC, requesting further research to improve diagnostic strategies and targeted therapies.