Overcoming intra-tumoral heterogeneity for biomarker discovery in the high-grade serous ovarian cancer proteome

Srikanth S Manda; Maiken M Espersen; Cristina Mapagu; Natalie Bouantoun; Jessica Boros; Yoke-Eng Chiew; Sivatharsny Srirangan; Swetansu Pattnaik; Catherine J Kennedy; Alison H Brand; Dale W Garsed; Ahwan Pandey; David D L Bowtell; Australian Ovarian Cancer Study (AOCS) Group; Natasha Lucas; Dylan Xavier; Sadia Mahboob; Daniel Bucio-Noble; Brett Tully; Peter G Hains; Phillip J Robinson; Qing Zhong; Roger Reddel; Anna DeFazio; Rosemary L Balleine

doi:10.1038/s41698-025-00911-y

Overcoming intra-tumoral heterogeneity for biomarker discovery in the high-grade serous ovarian cancer proteome

NPJ Precis Oncol. 2025 Jun 11;9(1):172. doi: 10.1038/s41698-025-00911-y.

Authors

Srikanth S Manda¹, Maiken M Espersen², Cristina Mapagu^{2

3

4}, Natalie Bouantoun^{2

3}, Jessica Boros², Yoke-Eng Chiew^{2

5}, Sivatharsny Srirangan^{2

3}, Swetansu Pattnaik⁶, Catherine J Kennedy^{2

3

5}, Alison H Brand^{3

5}, Dale W Garsed^{7

8}, Ahwan Pandey^{7

8}, David D L Bowtell^{7

8}; Australian Ovarian Cancer Study (AOCS) Group; Natasha Lucas¹, Dylan Xavier¹, Sadia Mahboob¹, Daniel Bucio-Noble¹, Brett Tully¹, Peter G Hains¹, Phillip J Robinson¹, Qing Zhong¹, Roger Reddel¹, Anna DeFazio^#^{9

10

11

12}, Rosemary L Balleine^#^{13

14

15}

Affiliations

¹ ProCan®, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.
² Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia.
³ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁴ Department of Medical Oncology, Nepean Hospital, Kingswood, NSW, Australia.
⁵ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia.
⁶ Garvan Institute for Medical Research, Darlinghurst, Sydney, NSW, Australia.
⁷ Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
⁸ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkvile, VIC, Australia.
⁹ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia. anna.defazio@sydney.edu.au.
¹⁰ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. anna.defazio@sydney.edu.au.
¹¹ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia. anna.defazio@sydney.edu.au.
¹² The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia. anna.defazio@sydney.edu.au.
¹³ ProCan®, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia. rosemary.balleine@sydney.edu.au.
¹⁴ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW, Australia. rosemary.balleine@sydney.edu.au.
¹⁵ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. rosemary.balleine@sydney.edu.au.

^# Contributed equally.

Abstract

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.

Abstract

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