Decoding the Genomic and Functional Landscape of Emerging Subtypes in Ovarian Cancer - UTU Research Portal

A1 Refereed original research article in a scientific journal

Decoding the Genomic and Functional Landscape of Emerging Subtypes in Ovarian Cancer

Authors: Micoli, Giulia; Lavikka, Kari; Li, Yilin; Pirttikoski, Anna; Afenteva, Daria; Senkowski, Wojciech; Marchi, Giovanni; Vähärautio, Anna; Muranen, Taru A.; Joutsiniemi, Titta; Hietanen, Sakari; Virtanen, Anni; Wennerberg, Krister; Hynninen, Johanna; Oikkonen, Jaana; Hautaniemi, Sampsa

Publisher: American Association for Cancer Research (AACR)

Publication year: 2025

Journal: Cancer Discovery

Volume: 15

Issue: 11

First page : 2262

Last page: 2277

ISSN: 2159-8274

eISSN: 2159-8290

DOI: https://doi.org/10.1158/2159-8290.CD-25-0652

Publication's open availability at the time of reporting: Open Access

Publication channel's open availability : Partially Open Access publication channel

Web address : https://doi.org/10.1158/2159-8290.cd-25-0652

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/505187695

Abstract

Ovarian high-grade serous carcinoma (HGSC) is characterized by pervasive genomic instability and high inter- and intra-tumor heterogeneity. Approximately half of HGSC tumors harbor homologous recombination deficiency (HRD), rendering them vulnerable to PARP inhibitors and platinum-based chemotherapy. In contrast, patients lacking HRD (HR-proficient, HRP) generally respond poorly to current therapies. To overcome heterogeneity and identify relevant HGSC subtypes, we characterized the genomic landscape of 640 tumors from 243 patients using whole-genome sequencing. Our chromosomal instability signature–based analysis characterized the structural variation landscape and revealed five HGSC subtypes, validated in an independent dataset. Two HRD subtypes, associated with BRCA1- or BRCA2-driven alterations, demonstrated favorable treatment responses. Strikingly, three HRP subtypes emerged, marked by unique structural alterations and gene expression patterns, tumor microenvironment interactions, and different chemotherapy responses. Notably, organoid experiments showed subtype-specific sensitivity to CHK1 inhibition, suggesting prexasertib as a potential targeted treatment for most currently untreatable HRP patients.

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Funding information in the publication:
This work was supported by the European Union’s Horizon 2020 Research and Innovative Program under grant agreement 965193 (DECIDER), the Sigrid Jusélius Foundation, Cancer Foundation Finland, the Novo Nordisk Foundation (NNF21OC0070381), European Union’s Horizon 2020 Research and Innovation Program (845045), the Danish Cancer Society (grant R204-A12322), and the OvaCure Foundation (The OvaCure Collection Initiative).