Overcoming intra-tumoral heterogeneity for biomarker discovery in the High-Grade Serous Ovarian Cancer proteome

Improved biomarkers of treatment response are needed for patients with High-Grade Serous Ovarian Cancer (HGSC). A challenge is substantial anatomical site-to-site variation in expression. We completed Data Independent Acquisition – Mass Spectrometry (DIA-MS) analysis of over 404 fresh frozen and 78 formalin fixed, paraffin-embedded HGSC tissue samples from ovary (adnexal) and a common secondary site (omentum) in 11 patients. This was compared with mutation testing, gene expression and whole genome copy number profiling. Proteins with relatively stable intra-, and variable inter-individual expression (n=1,651), included a 52-protein module reflecting interferon mediated tissue inflammation indicative of a cGAS-STING pathway cytosolic double-stranded (ds) DNA response. The dsDNA sensing / inflammation (DSI) score was higher in omentum compared with ovary. Ovarian HGSC samples showed marked inter-individual differences in inflammatory and immune responses to DNA damage. Stable discriminative features of the HGSC proteome, a prerequisite for clinical predictive biomarkers, are detectable in ovary (adnexal) tissue samples. Overall design: In this multi-omic study of High Grade Serous Ovarian cancer (HGSC), RNA Seq profiles were generated from Fresh Frozen Tissue samples of HGSC from matched primary site (ovary / adexa) and a common secondary site (omentum) in 11 patients.