NPJ precision oncology · 2025
Overcoming intra-tumoral heterogeneity for biomarker discovery in the high-grade serous ovarian cancer proteome.
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Manda Srikanth S, Espersen Maiken M, Mapagu Cristina, Bouantoun Natalie, Boros Jessica, Chiew Yoke-Eng, Srirangan Sivatharsny, Pattnaik Swetansu, Kennedy Catherine J, Brand Alison H, Garsed Dale W, Pandey Ahwan, Bowtell David D L, Australian Ovarian Cancer Study (AOCS) Group, Lucas Natasha, Xavier Dylan, Mahboob Sadia, Bucio-Noble Daniel, Tully Brett, Hains Peter G, Robinson Phillip J, Zhong Qing, Reddel Roger, DeFazio Anna, Balleine Rosemary L
Аннотация
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 404 fresh frozen and 78 formalin-fixed, paraffin-embedded HGSC tissue samples from the 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 = 1651), 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 score was higher in the omentum compared with the 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.