ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Molecular Targets and Therapeutics
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1633410
This article is part of the Research TopicExploring Molecular Mechanisms in Cancer through Tumor Molecular PathologyView all 8 articles
Genomic instability and CCNE1 amplification as emerging biomarkers for stratifying High-Grade Serous Ovarian Cancer
Provisionally accepted
Elena ConcaDaniele Lorenzini
Emanuela Minna
Luca Agnelli
Matteo Duca
Marco Gentili
Beatrice BodiniMaggie PolignanoMara MantieroSilvia DamianAndrea DevecchiRita CarminatiAlice ArdoreFrancesca Barbetta
Gian Paolo DagradaNathalia Brito Da CunhaAndrea Guerrizio
Adele BusicoIolanda CaponeAlberta Piccolo
Elena Tamborini
Federica Perrone
Massimo MilioneBiagio PaoliniAndrea VingianiFrancesco Raspagliesi
Filippo De Braud
Giancarlo Pruneri*- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Ovarian cancer (OC) is one of the leading causes of cancer-related death in women worldwide. Treatment with PARP-inhibitors has significantly improved survival in patients with high-grade serous cancer (HGSC) bearing BRCA1/2 mutations (~22% of the cases), and/or homologous recombination deficiency (HRD, ~50%). Unfortunately, limited therapeutic alternatives are available for BRCA1/2 wild type/HR proficient HGSC patients, who usually exhibit resistance to standard treatments and poor prognosis. Herein, we present the results of a comprehensive genomic profiling (CGP) analysis using the Oncomine Comprehensive Assay® (OCA) plus in a consecutive retrospective cohort of 102 HGSC patients characterized in our institution. Genomic instability, measured by Genomic Instability Metric, (GIM) >16 was found in 40% of the cases, and it was significantly associated with BRCA1/2 mutations (p=0.009) with a better prognosis in terms of recurrence-free survival (p=0.01). CCNE1 amplification, was observed in 29% of cases and it was negatively correlated with BRCA1/2 mutations (p=0.001) without any association with GIM, supporting CCNE1 as a strong and independent driver of tumorigenesis. Additionally, CCNE1 amplification was validated with fluorescent in situ hybridization (FISH), supporting the analytical robustness of NGS data (rho=0.93), and investigated by immunohistochemistry (IHC) raising intriguing questions about the role of CCNE1 in driving tumorigenesis, since CCNE1 protein overexpression was observed in absence of gene amplification in 45% of cases. Our real-world study supports the clinical utility of the GIM metric and the analytical validity of CCNE1 amplification, a new promising biomarker for personalizing treatment in HR proficient HGSC patients.
Keywords: high-grade serous ovarian cancer (HGSC), Comprehensive genomic profiling (CGP), Homologous Recombination Deficiency (HRD) score, CCNE1 amplification, Precision Oncology Cancer
Received: 22 May 2025; Accepted: 30 Jun 2025.
Copyright: © 2025 Conca, Lorenzini, Minna, Agnelli, Duca, Gentili, Bodini, Polignano, Mantiero, Damian, Devecchi, Carminati, Ardore, Barbetta, Dagrada, Brito Da Cunha, Guerrizio, Busico, Capone, Piccolo, Tamborini, Perrone, Milione, Paolini, Vingiani, Raspagliesi, De Braud and Pruneri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Giancarlo Pruneri, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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