High-grade serous ovarian cancers with brain metastases have a distinct copy number profile

Abstract

Background: Brain metastases (BM) from ovarian high-grade serous carcinoma (HGSC) are rare and associated with poor prognosis. As part of a multi-centre international study, we previously identified BRCA1/2 mutation enrichment in HGSC with BM through whole-exome sequencing (WES). We now extend this analysis to explore copy number (CN) alterations of these tumours and their temporal dynamics. Method(s): Formalin-fixed paraffin-embedded (FFPE) surgical samples of HGSC were collected at diagnosis (primary tumour) and from BM for 17 patients, yielding a total of 29 samples (12 matched pairs and 5 unmatched samples). Shallow whole genome sequencing (sWGS) was performed, applying a validated analytical pipeline to define CN features (Smith et al., 2023). CN profiles from this cohort were compared to the TCGA and BriTROC-1 datasets, which include unselected patients primarily with peritoneal-only disease. Result(s): Analysis of matched samples revealed stable CN profiles, with no significant differences in CN signatures, genome-wide CN profiles, or focal amplifications and deletions in key genes, suggesting that there is no specific CN change or evolution that drives central nervous system involvement. Across the entire BM cohort, we observed recurrent amplifications in MYC (17%), MECOM and PIK3CA (10%). In contrast, amplifications in CCNE1, AKT1 and BRCA1, as well as deletions in PTEN, were detected in fewer than 5% of cases. When comparing the BM cohort to the TCGA dataset, we observed distinct focal CN alterations-specifically, fewer CCNE1 amplifications and more PTEN deletions in the BM group. We also compared our CN data with the BriTROC-1 dataset, showing that our BM cohort exhibits distinct CN signatures, with a lower exposure to CN signature 2 (two-sided Wald test adjusted for multiple comparisons), characterised by large tandem duplication through CDK12 inactivation. Conclusion(s): Our analysis indicates that HGSC with BM constitutes a biologically different subgroup, defined by a unique CN profile. For this reason, assessing it with sWGS might become a powerful and inexpensive tool to identify women at increased risk of central nervous system involvement, who could benefit from personalised monitoring and targeted medications. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: G. Giannone: Financial Interests, Personal, Invited Speaker: MIT, Pharma&, Collage SPA. L. Tookman: Financial Interests, Personal, Invited Speaker, Honoraria for talks/presentations: AstraZeneca; Financial Interests, Personal, Invited Speaker, Honoraria for presentations: GSK; Financial Interests, Personal, Advisory Board, Olaparib for ovarian cancer: AstraZeneca; Financial Interests, Personal, Invited Speaker, honoraria for presentation on HRD testing: MSD; Financial Interests, Personal, Advisory Board, Dostarlimab for endometrial cancer: GSK; Financial Interests, Personal, Advisory Board, Advisory board for rucaparib (Athena clinical trial): Clovis Oncology; Financial Interests, Personal, Invited Speaker, Honoraria for talks and presentations: Clovis Oncology; Financial Interests, Personal, Invited Speaker, endometrial real world data project ovarian cancer perspective survey: GSK; Financial Interests, Institutional, Invited Speaker, AtTEND clinical trial: F. Hoffmann-La Roche; Non-Financial Interests, Personal, Advisory Role, Expert for NICE technology Appraisal for Dostarlimab: GSK; Other, Personal, Other, Travel and congress sponsorship: MSD. G. Valabrega: Financial Interests, Personal, Advisory Board: GSK, Regeneron, MSD, AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca. I. McNeish: Financial Interests, Personal, Advisory Board, Advisory Boards and travel: AstraZeneca, GSK; Financial Interests, Personal, Advisory Board: Roche, Alkermes, OncoC4, Theolytics; Financial Interests, Personal, Advisory Board, Advisory and consultancy on development of novel therapeutics in ovarian cancer: Duke Street Bio; Financial Interests, Personal, Advisory Board, Advice ahead of NICE submission: Pharma&; Financial Interests, Personal, Advisory Board, Advisory Board: BioNTech; Financial Interests, Institutional, Funding: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, Trustee of this charity: Worldwide Cancer Research. All other authors have declared no conflicts of interest.Copyright © 2025