Abstract
BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.
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Data availability
Short survival BRCA dataset: WGS, RNA-seq and SNP array data from short-term survivors generated as part of the current study have been deposited in the European Genome-phenome Archive (EGA) repository (https://ega-archive.org) under accession code EGAS00001008059. WGS and RNA-seq data are available as raw FASTQ files for each sample type (tumor/normal) and SNP array data are available as raw signal intensity files in text format for each sample type (tumor/normal). Controlled access to patient sequence data can be gained for academic use via the EGA, typically for a period of five years from the date the data transfer agreement is fully executed. Information on how to apply for access is available at the EGA under accession code EGAS00001008059. Responses to data requests will be provided within ten business days. The raw methylation data sets have been submitted to the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) under accession code GSE292140 with no access restrictions. ICGC dataset: Previously published WGS and RNA-seq data generated as part of the ICGC Ovarian Cancer project61 are available from the EGA repository as a single bam file for each sample type (tumor/normal), under the accession code EGAD00001000877. Due to the sensitive nature of these patient datasets, access is subject to approval from the ICGC Data Access Compliance Office, an independent body who authorizes controlled access to ICGC sequencing data. ICGC SNP array and methylation data sets have been deposited into GEO under accession code GSE65821, without access restrictions. ICGC gene count level transcriptomic data has been deposited into the GEO under accession code GSE209964. MOCOG dataset: WGS, RNA-seq and SNP array data from long-term survivors generated as part of the MOCOG study22 have been deposited in the EGA repository under accession code EGAS00001005984. WGS and RNA-seq data are available as raw FASTQ files for each sample type (tumor/normal) and SNP array data are available as raw signal intensity files in text format for each sample type (tumor/normal). Controlled access to patient sequence data can be gained for academic use via the EGA, typically for a period of five years from the date the data transfer agreement is fully executed. Information on how to apply for access is available at the EGA under accession code EGAS00001005984. Responses to data requests will be provided within ten business days. The MOCOG cohort raw methylation data sets have been submitted to the GEO under accession code GSE211687, with no access restrictions. Uniformly processed somatic variant data from the ICGC, MOCOG, and short survival BRCA cohorts is deposited in Synapse under accession code syn65463502 and processed methylation and expression data from all cohorts has been submitted into the GEO under accession codes GSE292140 and GSE292142, without access restrictions. OTTA dataset: The data underlying the figures and tables are provided in the Source Data file. Population frequencies of genetic variants can be accessed via the Genome Aggregation Database (gnomAD) at https://gnomad.broadinstitute.org/. Supporting evidence for pathogenicity of genomic alterations can be accessed via ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), BRCA Exchange (https://brcaexchange.org/) and the TP53 Database (https://tp53.cancer.gov/). The Ensembl ranked order of severity of variant consequences is available at: https://www.ensembl.org/info/genome/variation/prediction/predicted_data.html. Mutational signature reference databases can be accessed via COSMIC (https://cancer.sanger.ac.uk/signatures/) and Signal (https://signal.mutationalsignatures.com/). The LM22 signature matrix used for immune cell deconvolution can be downloaded here: https://cibersortx.stanford.edu/. MSigDB hallmark gene sets can be accessed here: https://www.gsea-msigdb.org/gsea/msigdb/. Illumina methylation probes that were filtered out due to poor performance (e.g., cross reactive or non-specific probes) can be found here: https://github.com/sirselim/illumina450k_filtering. Germline polymorphic sites for reference and variant allele read counts used in FACETS analysis can be found at https://ftp.ncbi.nih.gov/snp/organisms/human_9606_b151_GRCh37p13/VCF/common_all_20180423.vcf.gz. The GTF used for annotation and RNA-seq counts is available here: https://ftp.ensembl.org/pub/grch37/release-92/. All other data are available within the article and its Supplementary and Source Data files. Source data are provided with this paper.
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Acknowledgements
We thank A. Freimund, R. Lupat, J. Ellul, and the Peter MacCallum Cancer Centre Research Computing Facility for their contributions to the study. This work was supported by the National Health and Medical Research Council (NHMRC) of Australia (GNT1186505 and GNT2029088), the US Army Medical Research and Materiel Command Ovarian Cancer Research Program (Award No. W81XWH-16-2-0010 and W81XWH-21-1-0401), the National Institutes of Health (NIH) (R21-CA267050, K07-CA080668, R01-CA95023, R01-CA248288, P50-CA136393, P30-CA015083, MO1-RR000056), the Swiss National Foundation (P500PM_20726); Bangerter-Rhyner Stiftung (0297); Margarete and Walter Lichtenstein-Stiftung; and Freie Gesellschaft Basel. The Gynecological Oncology Biobank at Westmead was funded by the NHMRC (ID310670, ID628903); the Cancer Institute NSW (12/RIG/1-17, 15/RIG/1-16); the Department of Gynaecological Oncology, Westmead Hospital; and acknowledges financial support from the Sydney West Translational Cancer Research Centre, funded by the Cancer Institute NSW (15/TRC/1-01). Direct funding for the generation of the NanoString data for OTTA was provided by the NIH (R01-CA172404, and R01-CA168758), the Canadian Institutes for Health Research (Proof-of-Principle I program) and the United States Department of Defense Ovarian Cancer Research Program (OC110433). T.A.Z. is supported by the Swiss National Foundation Return CH Postdoc.Mobility (P5R5PM_222151). D.W.G. is supported by a Victorian Cancer Agency/Ovarian Cancer Australia Low-Survival Cancer Philanthropic Mid-Career Research Fellowship (MCRF22018) and the Ovarian Cancer Research Foundation (2025/OCRF0071). S.J.R. is supported by the NHMRC (2009840). M.J.G is supported by the Ministerio de Ciencia, Innovación y Universidades (MICIU)/AEI/10.13039/501100011033 and ERDF, EU (Project PID2023-151298OB-I00). A.O. is partially funded by Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (PI23/01235) supported by FEDER funds and the Spanish Network on Rare Diseases (CIBERER). K.M.D., T.P.C., and G.L.M. were supported by awards from the Uniformed Services University of the Health Sciences and the Defense Health Program to the Henry M Jackson Foundation (HJF) for the Advancement of Military Medicine Inc. to the Gynecologic Cancer Center of Excellence Program including HU0001-16-2-0006 (PIs: Chad A. Hamilton and G. Larry Maxwell), HU0001-19-2-0031, HU0001-20-2-0033, and HU0001-21-2-0027 (PIs: Yovanni Casablanca and G. Larry Maxwell), HU0001-22-2-0016 and HU0001-23-2-0038 (PIs: Neil T. Phippen and G. Larry Maxwell), as well as HU0001-23-2-0038 and HU0001-24-2-0047 (PIs Christopher M Tarney and G. Larry Maxwell). T.V.G. is a Senior Clinical Investigator of the Fund for Scientific Research-Flanders (FWO Vlaanderen 18B2921N). A.DeF. is supported by the NHMRC (2033042). The AOV study was funded by the Canadian Institutes for Health Research (MOP-86727). The Generations Study was funded by Breast Cancer Now and the United Kingdom National Health Service funding to the Royal Marsden/Institute of Cancer Research. The UK Ovarian Cancer Population study (UKOPS) was funded by The Eve Appeal (The Oak Foundation) with contribution to authors’ salary through MRC core funding MC_UU_00004/01 and the NIH Research University College London Hospitals Biomedical Research Centre. The contents of the published material are solely the responsibility of the authors and do not reflect the views of the NHMRC, NIH, and other funders.
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T. A. Z.: Conceptualization, data curation, formal analysis, funding acquisition, validation, investigation, visualization, methodology, writing–original draft, writing–review and editing. S.F.: Conceptualization, data curation, validation, methodology, writing–original draft, writing–review and editing. A.P.: Conceptualization, data curation, formal analysis, validation, investigation, visualization, methodology, writing–original draft, writing–review and editing. D.A.: Data curation, validation, investigation, visualization, methodology, writing–original draft, writing–review and editing. M.W.J.: Formal analysis, validation, investigation, visualization, methodology, writing–original draft, writing–review and editing. L.T.: Formal analysis, validation, investigation, visualization, methodology, writing–original draft, writing–review and editing. A.F.: Conceptualization, data curation, investigation, writing–review and editing. C.M.L.: Formal analysis, validation, investigation, methodology, writing–review and editing. C.J.K.: Resources, data curation, methodology, writing–original draft, writing–review and editing. A.B.: Resources, writing–review and editing. N.S.M.: Resources, writing–review and editing. K.M.: Resources, writing–review and editing. P.H.: Data curation, formal analysis, validation, investigation, methodology, writing–review and editing. J.A.: Resources, writing–review and editing. A.C.A.: Resources, writing–review and editing. G.A-Y.: Resources, writing–review and editing. M.W.B.: Resources, writing–review and editing. A.B.: Resources, writing–review and editing. C.B.: Resources, writing–review and editing. F.B.: Resources, writing–review and editing. C.B.: Resources, writing–review and editing. J.B.: Resources, writing–review and editing. A.H.B.: Resources, writing–review and editing. M.E.C.: Resources, writing–review and editing. A.C-J.: Resources, writing–review and editing. 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T.A.Z. reports personal consulting fees from AbbVie that are outside the submitted work. D.D.L.B. reports research support grants from AstraZeneca, Roche-Genentech and BeiGene paid to institution outside the submitted work; also, personal consulting fees from Exo Therapeutics that are outside the submitted work. G.A.-Y. reports research support grants from AstraZeneca and Roche-Genentech paid to institution outside the submitted work; also, personal consulting fees from Incyclix Bio that are outside the submitted work. A.DeF. reports research support from AstraZeneca and Illumina. N.N. reports research support from Illumina. P.A.C. reports speakers’ honoraria from AstraZeneca, Merck Sharpe and Dohme, and GlaxoSmithKline, and personal consulting fees from Astra Zeneca outside the remit of the submitted work. U.M. and A.G.M. report personal consulting fees from Mercy BioAnalytics Ltd and research support grants from Intelligent Lab on Fiber, RNA Guardian, and MercyBio Analytics that are all outside the remit of the submitted work. E.L.C. reports research support from AstraZeneca paid to institution outside the submitted work and speakers’ honoraria from AstraZeneca and GSK. S.E.T reports consulting fees from AstraZeneca and IntegraConnect outside the submitted work. P.H. reports honoraria and consulting fees from Amgen, Astra Zeneca, GSK, Roche, Immunogen, Sotio, Stryker, ZaiLab, MSD, Clovis, Miltenyi, Eisai, Mersana, Exscientia, Daiichi Sankyo, Karyopharm, Abbvie, Novartis, Corcept, BionTech, Zymeworks and Research funding (Institutional) from Astra Zeneca, Roche, GSK, Genmab, Immunogen, Seagen, Clovis, Novartis, Immatics, Abbvie, MSD. I.V. has participated in consulting advisory boards for Akesobio, Bristol Myers Squibb, Eisai, F. Hoffmann-La Roche, Genmab, GSK, ITM, Karyopharm, MSD, Novocure, Oncoinvent, Sanofi, Regeneron, and Seagen, and has participated in consulting data monitoring committees for Abbvie, Agenus, AstraZeneca, Corcept, Daiichi, F. Hoffmann-La Roche, Immunogen, Kronos Bio, Mersana, Novartis, OncXerna, Verastem Oncology, and Zentalis. The remaining authors declare no competing interests.
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Zwimpfer, T.A., Fereday, S., Pandey, A. et al. Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71134-3
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DOI: https://doi.org/10.1038/s41467-026-71134-3


