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Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma
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  • Published: 01 April 2026

Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma

  • Tibor A. Zwimpfer1,2,3,
  • Sian Fereday  ORCID: orcid.org/0000-0002-8559-85791,4,
  • Ahwan Pandey  ORCID: orcid.org/0000-0003-2238-10541,
  • Dinuka Ariyaratne  ORCID: orcid.org/0000-0001-5704-90301,
  • Madawa W. Jayawardana1,4,
  • Laura Twomey1,
  • Céline M. Laumont  ORCID: orcid.org/0000-0002-9067-40545,
  • Catherine J. Kennedy6,7,8,
  • Adelyn Bolithon9,10,
  • Nicola S. Meagher  ORCID: orcid.org/0000-0001-9134-21189,11,
  • Katy Milne  ORCID: orcid.org/0000-0001-5616-18215,
  • Phineas Hamilton5,
  • Jennifer Alsop12,
  • Antonis C. Antoniou13,
  • George Au-Yeung  ORCID: orcid.org/0000-0003-1128-63851,4,
  • Matthias W. Beckmann14,
  • Amy Berrington de Gonzalez  ORCID: orcid.org/0000-0002-7332-838715,
  • Christiani Bisinotto16,
  • Freya Blome  ORCID: orcid.org/0009-0003-0866-702917,
  • Clara Bodelon  ORCID: orcid.org/0000-0002-6578-267818,
  • Jessica Boros6,7,8,
  • Alison H. Brand7,8,
  • Michael E. Carney19,
  • Alicia Cazorla-Jiménez20,
  • Derek S. Chiu21,
  • Elizabeth L. Christie  ORCID: orcid.org/0000-0002-9959-70241,4,
  • Anita Chudecka-Głaz22,
  • Penny Coulson15,
  • Kara L. Cushing-Haugen23,
  • Cezary Cybulski24,
  • Kathleen M. Darcy  ORCID: orcid.org/0000-0003-2888-296825,26,
  • Cath David27,
  • Trent Davidson28,29,
  • Arif B. Ekici  ORCID: orcid.org/0000-0001-6099-706630,
  • Esther Elishaev31,
  • Julius Emons14,
  • Tobias Engler  ORCID: orcid.org/0000-0002-8063-205332,
  • Rhonda Farrell8,33,
  • Anna Fischer17,
  • Montserrat García-Closas15,
  • Aleksandra Gentry-Maharaj34,35,
  • Prafull Ghatage  ORCID: orcid.org/0000-0002-2371-084436,
  • Rosalind Glasspool37,
  • Philipp Harter38,
  • Andreas D. Hartkopf32,39,
  • Arndt Hartmann40,
  • Sebastian Heikaus41,
  • Brenda Y. Hernandez42,
  • Anusha Hettiaratchi  ORCID: orcid.org/0000-0002-5928-230043,
  • Sabine Heublein44,
  • David G. Huntsman45,46,
  • Mercedes Jimenez-Linan47,
  • Michael E. Jones  ORCID: orcid.org/0000-0001-7479-345115,
  • Eunyoung Kang48,
  • Ewa Kaznowska49,
  • Tomasz Kluz50,
  • Felix K. F. Kommoss  ORCID: orcid.org/0000-0003-0876-908751,
  • Gottfried Konecny  ORCID: orcid.org/0000-0001-6083-657X52,
  • Roy F. P. M. Kruitwagen53,54,
  • Jessica Kwon45,
  • Diether Lambrechts  ORCID: orcid.org/0000-0002-3429-302X55,56,
  • Cheng-Han Lee  ORCID: orcid.org/0000-0003-2094-122257,
  • Jenny Lester52,
  • Samuel C. Y. Leung21,
  • Yee Leung  ORCID: orcid.org/0000-0003-0349-865258,59,
  • Anna Linder  ORCID: orcid.org/0000-0002-9444-134660,
  • Jolanta Lissowska61,
  • Liselore Loverix62,
  • Jan Lubiński63,
  • Constantina Mateoiu64,
  • Iain A. McNeish  ORCID: orcid.org/0000-0002-9387-758665,66,
  • Malak Moubarak38,
  • Gregg S. Nelson  ORCID: orcid.org/0000-0002-8177-109836,
  • Nikilyn Nevins  ORCID: orcid.org/0000-0002-5744-42816,7,8,
  • Alexander B. Olawaiye67,
  • Siel Olbrecht62,
  • Sandra Orsulic  ORCID: orcid.org/0000-0001-5119-872152,
  • Ana Osorio68,69,
  • Carmel M. Quinn43,
  • Ganendra Raj Mohan58,70,
  • Isabelle Ray-Coquard  ORCID: orcid.org/0000-0003-2472-830671,
  • Cristina Rodríguez-Antona69,72,
  • Patricia Roxburgh  ORCID: orcid.org/0000-0001-9869-591X66,
  • Matthias Ruebner14,
  • Stuart G. Salfinger70,
  • Spinder Samra6,8,73,
  • Minouk J. Schoemaker15,
  • Hans-Peter Sinn  ORCID: orcid.org/0000-0003-2836-669951,
  • Gabe S. Sonke  ORCID: orcid.org/0000-0001-8088-962874,
  • Linda Steele75,
  • Colin J. R. Stewart59,
  • Aline Talhouk21,45,
  • Adeline Tan59,76,
  • Christopher M. Tarney25,
  • Sarah E. Taylor67,
  • Koen K. Van de Vijver  ORCID: orcid.org/0000-0002-2026-979077,78,
  • Maaike A. van der Aa79,
  • Toon Van Gorp  ORCID: orcid.org/0000-0002-2564-721X80,
  • Els Van Nieuwenhuysen62,
  • Lilian Van-Wagensveld53,54,79,
  • Andrea E. Wahner-Hendrickson81,
  • Christina Walter32,
  • Chen Wang  ORCID: orcid.org/0000-0003-2638-308182,
  • Julia Welz38,
  • Nicolas Wentzensen  ORCID: orcid.org/0000-0003-1251-083683,
  • Lynne R. Wilkens42,
  • Stacey J. Winham82,
  • Boris Winterhoff84,
  • Michael S. Anglesio  ORCID: orcid.org/0000-0003-1639-500321,45,
  • Andrew Berchuck85,
  • Francisco J. Candido dos Reis16,
  • Paul A. Cohen  ORCID: orcid.org/0000-0002-4860-923258,59,
  • Thomas P. Conrads  ORCID: orcid.org/0000-0003-4742-328125,86,
  • Philip Crowe9,
  • Jennifer A. Doherty87,
  • Peter A. Fasching  ORCID: orcid.org/0000-0003-4885-847114,
  • Renée T. Fortner88,89,
  • María J. García90,
  • Simon A. Gayther91,
  • Marc T. Goodman92,
  • Jacek Gronwald63,
  • Holly R. Harris23,93,
  • Florian Heitz38,41,94,
  • Hugo M. Horlings  ORCID: orcid.org/0000-0003-4782-882895,
  • Beth Y. Karlan  ORCID: orcid.org/0000-0002-9451-293352,
  • Linda E. Kelemen96,
  • G. Larry Maxwell25,86,
  • Usha Menon  ORCID: orcid.org/0000-0003-3708-173234,
  • Francesmary Modugno67,97,98,
  • Susan L. Neuhausen  ORCID: orcid.org/0000-0001-5053-039075,
  • Joellen M. Schildkraut99,
  • Annette Staebler17,
  • Karin Sundfeldt60,
  • Anthony J. Swerdlow15,100,
  • Ignace Vergote62,
  • Anna H. Wu101,
  • James D. Brenton  ORCID: orcid.org/0000-0002-5738-6683102,
  • Paul D. P. Pharoah  ORCID: orcid.org/0000-0001-8494-732X103,
  • Celeste Leigh Pearce104,
  • Malcolm C. Pike101,105,
  • Ellen L. Goode  ORCID: orcid.org/0000-0002-9094-8326106,
  • Susan J. Ramus  ORCID: orcid.org/0000-0003-0005-77989,10,
  • Martin Köbel  ORCID: orcid.org/0000-0002-6615-2037107,
  • Brad H. Nelson  ORCID: orcid.org/0000-0002-4445-55395,108,109,
  • Anna DeFazio  ORCID: orcid.org/0000-0003-0057-47446,7,8,11,
  • Michael L. Friedlander  ORCID: orcid.org/0000-0003-3090-795X27,110,111,
  • David D. L. Bowtell1,4 &
  • …
  • Dale W. Garsed  ORCID: orcid.org/0000-0003-1223-01211,4 

Nature Communications (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer genetics
  • Cancer genomics
  • DNA sequencing
  • Ovarian cancer
  • RNA sequencing

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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Authors and Affiliations

  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Tibor A. Zwimpfer, Sian Fereday, Ahwan Pandey, Dinuka Ariyaratne, Madawa W. Jayawardana, Laura Twomey, George Au-Yeung, Elizabeth L. Christie, David D. L. Bowtell & Dale W. Garsed

  2. Department of Biomedicine, University of Basel, Basel, Switzerland

    Tibor A. Zwimpfer

  3. Gynecological Cancer Centre, University Hospital Basel, Basel, Switzerland

    Tibor A. Zwimpfer

  4. The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia

    Sian Fereday, Madawa W. Jayawardana, George Au-Yeung, Elizabeth L. Christie, David D. L. Bowtell & Dale W. Garsed

  5. Deeley Research Centre, BC Cancer, Victoria, BC, Canada

    Céline M. Laumont, Katy Milne, Phineas Hamilton & Brad H. Nelson

  6. Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW, Australia

    Catherine J. Kennedy, Jessica Boros, Nikilyn Nevins, Spinder Samra & Anna DeFazio

  7. Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia

    Catherine J. Kennedy, Jessica Boros, Alison H. Brand, Nikilyn Nevins & Anna DeFazio

  8. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia

    Catherine J. Kennedy, Jessica Boros, Alison H. Brand, Rhonda Farrell, Nikilyn Nevins, Spinder Samra & Anna DeFazio

  9. School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia

    Adelyn Bolithon, Nicola S. Meagher, Philip Crowe & Susan J. Ramus

  10. Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, 2052, Australia

    Adelyn Bolithon & Susan J. Ramus

  11. The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia

    Nicola S. Meagher & Anna DeFazio

  12. Department of Oncology, University of Cambridge, Cambridge, UK

    Jennifer Alsop

  13. Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK

    Antonis C. Antoniou

  14. Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg. University Hospital Erlangen, Erlangen, Germany

    Matthias W. Beckmann, Julius Emons, Matthias Ruebner & Peter A. Fasching

  15. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK

    Amy Berrington de Gonzalez, Penny Coulson, Montserrat García-Closas, Michael E. Jones, Minouk J. Schoemaker & Anthony J. Swerdlow

  16. Department of Gynecology and Obstetrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil

    Christiani Bisinotto & Francisco J. Candido dos Reis

  17. Institute of Pathology and Neuropathology, Tuebingen University Hospital, Tuebingen, Germany

    Freya Blome, Anna Fischer & Annette Staebler

  18. Department of Population Science, American Cancer Society, Atlanta, GA, USA

    Clara Bodelon

  19. Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    Michael E. Carney

  20. Pathology Department, Fundación Jiménez Díaz, Madrid, Spain

    Alicia Cazorla-Jiménez

  21. British Columbia’s Gynecological Cancer Research Team OVCARE, University of British Columbia, BC Cancer and Vancouver General Hospital, Vancouver, BC, Canada

    Derek S. Chiu, Samuel C. Y. Leung, Aline Talhouk & Michael S. Anglesio

  22. Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland

    Anita Chudecka-Głaz

  23. Division of Public Health Sciences, Program in Epidemiology, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Kara L. Cushing-Haugen & Holly R. Harris

  24. Department of Comparative Biomedical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS, USA

    Cezary Cybulski

  25. Department of Gynecologic Surgery and Obstetrics, Gynecologic Cancer Center of Excellence, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, USA

    Kathleen M. Darcy, Christopher M. Tarney, Thomas P. Conrads & G. Larry Maxwell

  26. IHenry M Jackson Foundation for the Advancement of Military Medicine, nc, Bethesda, MD, USA

    Kathleen M. Darcy

  27. Gynaecological Cancer Centre, Royal Hospital for Women, Randwick, NSW, Australia

    Cath David & Michael L. Friedlander

  28. NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, Australia

    Trent Davidson

  29. School of Medicine, Western Sydney University, Penrith, NSW, Australia

    Trent Davidson

  30. Institute of Human Genetics. Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg FAU, Erlangen, Germany

    Arif B. Ekici

  31. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Esther Elishaev

  32. Department of Women’s Health, Tuebingen University Hospital, Tuebingen, Germany

    Tobias Engler, Andreas D. Hartkopf & Christina Walter

  33. Prince of Wales Private Hospital, Randwick, NSW, Australia

    Rhonda Farrell

  34. MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK

    Aleksandra Gentry-Maharaj & Usha Menon

  35. Department of Women’s Cancer, Elizabeth Garrett Anderson Institute for Women’s Health, University College London, London, UK

    Aleksandra Gentry-Maharaj

  36. Division of Gynecologic Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    Prafull Ghatage & Gregg S. Nelson

  37. Beatson West of Scotland Cancer Centre and School of Cancer Sciences, University of Glasgow, Glasgow, UK

    Rosalind Glasspool

  38. Department of Gynecology and Gynecologic Oncology, Evangelische Kliniken Essen-Mitte, Essen, Germany

    Philipp Harter, Malak Moubarak, Julia Welz & Florian Heitz

  39. Department of Gynecology and Obstetrics, University Hospital of Ulm, Ulm, Germany

    Andreas D. Hartkopf

  40. Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany

    Arndt Hartmann

  41. Center for Pathology, Evangelische Kliniken Essen-Mitte, Essen, Germany

    Sebastian Heikaus & Florian Heitz

  42. University of Hawaii Cancer Center, Honolulu, HI, USA

    Brenda Y. Hernandez & Lynne R. Wilkens

  43. The Health Precincts Biobank, UNSW Biospecimen Services, Mark Wainwright Analytical Centre, UNSW, Sydney, NSW, Australia

    Anusha Hettiaratchi & Carmel M. Quinn

  44. Department of Obstetrics and Gynecology, University Hospital Heidelberg, Heidelberg, Germany

    Sabine Heublein

  45. Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada

    David G. Huntsman, Jessica Kwon, Aline Talhouk & Michael S. Anglesio

  46. Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada

    David G. Huntsman

  47. Department of Histopathology, Addenbrooke’s Hospital, Cambridge, UK

    Mercedes Jimenez-Linan

  48. Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea

    Eunyoung Kang

  49. Department of Pathology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland

    Ewa Kaznowska

  50. Department of Gynecology, Gynecology Oncology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszów University, Rzeszów, Poland

    Tomasz Kluz

  51. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany

    Felix K. F. Kommoss & Hans-Peter Sinn

  52. Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

    Gottfried Konecny, Jenny Lester, Sandra Orsulic & Beth Y. Karlan

  53. Department of Obstetrics and Gynecology, Maastricht University Medical Centre, Maastricht, the Netherlands

    Roy F. P. M. Kruitwagen & Lilian Van-Wagensveld

  54. GROW Ð School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, the Netherlands

    Roy F. P. M. Kruitwagen & Lilian Van-Wagensveld

  55. Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium

    Diether Lambrechts

  56. VIB Center for Cancer Biology, VIB Leuven, Belgium

    Diether Lambrechts

  57. Department of Pathology and Laboratory Medicine, University of Alberta, Edmonton, AB, Canada

    Cheng-Han Lee

  58. Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, WA, Australia

    Yee Leung, Ganendra Raj Mohan & Paul A. Cohen

  59. Division of Obstetrics and Gynaecology, Medical School, University of Western Australia, Crawley, WA, Australia

    Yee Leung, Colin J. R. Stewart, Adeline Tan & Paul A. Cohen

  60. Department of Obstetrics and Gynecology, Institute of Clinical Science, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden

    Anna Linder & Karin Sundfeldt

  61. Department of Cancer Epidemiology and Prevention, M Sklodowska-Curie National Research Oncology Institute, Warsaw, Poland

    Jolanta Lissowska

  62. Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Leuven Cancer Institute, Leuven, Belgium

    Liselore Loverix, Siel Olbrecht, Els Van Nieuwenhuysen & Ignace Vergote

  63. Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

    Jan Lubiński & Jacek Gronwald

  64. Department of Pathology, University of Gothenburg, Gothenburg, Sweden

    Constantina Mateoiu

  65. Division of Cancer and Ovarian Cancer Action Research Centre, Department Surgery & Cancer, Imperial College London, London, UK

    Iain A. McNeish

  66. School of Cancer Sciences, University of Glasgow, Glasgow, UK

    Iain A. McNeish & Patricia Roxburgh

  67. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Alexander B. Olawaiye, Sarah E. Taylor & Francesmary Modugno

  68. Genetics Service, Fundación Jiménez Díaz University Hospital and Health Research Institute, Universidad Autónoma de Madrid IIS-FJD, UAM, Madrid, Spain

    Ana Osorio

  69. Centre for Biomedical Network Research on Rare Diseases CIBERER, Instituto de Salud Carlos III, Madrid, Spain

    Ana Osorio & Cristina Rodríguez-Antona

  70. Department of Gynaecological Oncology, St John of God Subiaco Hospital, Subiaco, WA, Australia

    Ganendra Raj Mohan & Stuart G. Salfinger

  71. Centre Leon Berard and University Claude Bernard Lyon 1, Lyon, France

    Isabelle Ray-Coquard

  72. Pharmacogenomics and Tumor Biomarkers Group, Institute for Biomedical Research Sols-Morreale CSIC-UAM, Madrid, Spain

    Cristina Rodríguez-Antona

  73. Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, NSW, Australia

    Spinder Samra

  74. Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Gabe S. Sonke

  75. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA

    Linda Steele & Susan L. Neuhausen

  76. Gynaepath WA, Clinipath Sonic Healthcare, Osbourne Park, Australia

    Adeline Tan

  77. Department of Pathology, Ghent University Hospital, Cancer Research Institute Ghent CRIG, Ghent, Belgium

    Koen K. Van de Vijver

  78. Department of Pathology, Antwerp University Hospital, Antwerp, Belgium

    Koen K. Van de Vijver

  79. Department of Research, Netherlands Comprehensive Cancer Organization IKNL, Utrecht, the Netherlands

    Maaike A. van der Aa & Lilian Van-Wagensveld

  80. Division of Gynaecological Oncology, Leuven Cancer Institute, University Hospital Leuven and KU Leuven, Leuven, Belgium

    Toon Van Gorp

  81. Department of Oncology, Mayo Clinic, Rochester, MN, USA

    Andrea E. Wahner-Hendrickson

  82. Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA

    Chen Wang & Stacey J. Winham

  83. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

    Nicolas Wentzensen

  84. Department of Obstetrics, Gynecology and Women’s Health, University of Minnesota, Minneapolis, MN, USA

    Boris Winterhoff

  85. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

    Andrew Berchuck

  86. Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA, USA

    Thomas P. Conrads & G. Larry Maxwell

  87. Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA

    Jennifer A. Doherty

  88. Division of Cancer Epidemiology, German Cancer Research Center DKFZ, Heidelberg, Germany

    Renée T. Fortner

  89. Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway

    Renée T. Fortner

  90. Genomic Biomarkers and Precision Oncology Group, Sols-Morreale Biomedical Research Institute IIBM, Consejo Superior de Investigaciones Cientficas & Universidad Autónoma de Madrid CSIC-UAM, Madrid, 28029, Spain

    María J. García

  91. Medicine, University of Texas Health, San Antonio, TX, USA

    Simon A. Gayther

  92. Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Marc T. Goodman

  93. Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA

    Holly R. Harris

  94. Department of Gynecology and Gynecological Oncology, HSK, Dr Horst-Schmidt Klinik, Wiesbaden, Wiesbaden, Germany

    Florian Heitz

  95. Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands

    Hugo M. Horlings

  96. Communicable Disease Epidemiology Section, South Carolina Department of Public Health, Columbia, SC, USA

    Linda E. Kelemen

  97. Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA

    Francesmary Modugno

  98. Women’s Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA

    Francesmary Modugno

  99. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA

    Joellen M. Schildkraut

  100. Division of Breast Cancer Research, The Institute of Cancer Research, London, UK

    Anthony J. Swerdlow

  101. Department of Population Health and Public Health Sciences, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    Anna H. Wu & Malcolm C. Pike

  102. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    James D. Brenton

  103. Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, USA

    Paul D. P. Pharoah

  104. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA

    Celeste Leigh Pearce

  105. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Malcolm C. Pike

  106. Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA

    Ellen L. Goode

  107. Department of Pathology and Laboratory Medicine, Foothills Medical Center, University of Calgary, Calgary, AB, Canada

    Martin Köbel

  108. Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada

    Brad H. Nelson

  109. Department of Medical Genetics, University of British Columbia, Victoria, BC, Canada

    Brad H. Nelson

  110. Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, NSW, Australia

    Michael L. Friedlander

  111. Prince of Wales Clinical School, UNSW Medicine and Health, University of NSW Sydney, Sydney, NSW, Australia

    Michael L. Friedlander

Authors
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Contributions

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. D.S.C.: Resources, writing–review and editing. E.L.C.: Resources, writing–review and editing. A.C-G.: Resources, writing–review and editing. P.C.: Resources, writing–review and editing. K.L.C-H.: Resources, writing–review and editing. C.C.: Resources, writing–review and editing. K.M.D.: Resources, writing–review and editing. C.D.: Resources, writing–review and editing. T.D.: Resources, writing–review and editing. A.B.E.: Resources, writing–review and editing. E.E.: Resources, writing–review and editing. J.E.: Resources, writing–review and editing. T.E.: Resources, writing–review and editing. R.F.: Resources, writing–review and editing. A.F.: Resources, writing–review and editing. M.G-C.: Resources, writing–review and editing. A.G-M.: Resources, writing–review and editing. P.G.: Resources, writing–review and editing. R.G.: Resources, writing–review and editing. P.H.: Resources, writing–review and editing. A.D.H.: Resources, writing–review and editing. A.H.: Resources, writing–review and editing. S.H.: Resources, writing–review and editing. B.Y.H.: Resources, writing–review and editing. A.H.: Resources, writing–review and editing. S.H.: Resources, writing–review and editing. D.G.H.: Resources, writing–review and editing. M.J-L.: Resources, writing–review and editing. M.E.J.: Resources, writing–review and editing. E.K.: Resources, writing–review and editing. E.K.: Resources, writing–review and editing. T.K.: Resources, writing–review and editing. F.K.F.K.: Resources, writing–review and editing. G.K.: Resources, writing–review and editing. R.F.P.M.K.: Resources, writing–review and editing. J.K.: Resources, writing–review and editing. D.L.: Resources, writing–review and editing. C-H.L.: Resources, writing–review and editing. J.L.: Resources, writing–review and editing. S.C.Y.L.: Resources, writing–review and editing. Y.L.: Resources, writing–review and editing. A.L.: Resources, writing–review and editing. J.L.: Resources, writing–review and editing. L.L.: Resources, writing–review and editing. J.L.: Resources, writing–review and editing. C.M.: Resources, writing–review and editing. I.A.M.: Resources, writing–review and editing. M.M.: Resources, writing–review and editing. G.S.N.: Resources, writing–review and editing. N.N.: Resources, writing–review and editing. A.O.: Resources, writing–review and editing. S.O.: Resources, writing–review and editing. A.O.: Resources, writing–review and editing. C.M.Q.: Resources, writing–review and editing. G.RM.: Resources, writing–review and editing. I.R-C.: Resources, writing–review and editing. C.R-A.: Resources, writing–review and editing. P.R.: Resources, writing–review and editing. M.R.: Resources, writing–review and editing. S.G.S.: Resources, writing–review and editing. S.S.: Resources, writing–review and editing. M.J.S.: Resources, writing–review and editing. H-P.S.: Resources, writing–review and editing. G.S.S.: Resources, writing–review and editing. L.S.: Resources, writing–review and editing. C.J.R.S.: Resources, writing–review and editing. A.T.: Resources, writing–review and editing. A.T.: Resources, writing–review and editing. C.M.T.: Resources, writing–review and editing. S.E.T.: Resources, writing–review and editing. K.K.V.: Resources, writing–review and editing. M.A.A.: Resources, writing–review and editing. T.G.: Resources, writing–review and editing. E.N.: Resources, writing–review and editing. L.W.: Resources, writing–review and editing. A.E.W-H.: Resources, writing–review and editing. C.W.: Resources, writing–review and editing. C.W.: Resources, writing–review and editing. J.W.: Resources, writing–review and editing. N.W.: Resources, writing–review and editing. L.R.W.: Resources, writing–review and editing. S.J.W.: Resources, writing–review and editing. B.W.: Resources, writing–review and editing. M.S.A.: Resources, writing–review and editing. A.B.: Resources, writing–review and editing. F.J.C-R.: Resources, writing–review and editing. P.A.C.: Resources, writing–review and editing. T.P.C.: Resources, writing–review and editing. P.C.: Resources, writing–review and editing. J.A.D.: Resources, writing–review and editing. P.A.F.: Resources, writing–review and editing. R.T.F.: Resources, writing–review and editing. M.J.G.: Resources, writing–review and editing. S.A.G.: Resources, writing–review and editing. M.T.G.: Resources, writing–review and editing. J.G.: Resources, writing–review and editing. H.R.H.: Resources, writing–review and editing. F.H.: Resources, writing–review and editing. H.M.H.: Resources, writing–review and editing. B.Y.K.: Resources, writing–review and editing. L.E.K.: Resources, writing–review and editing. G.L.M.: Resources, writing–review and editing. U.M.: Resources, writing–review and editing. F.M.: Resources, writing–review and editing. S.L.N.: Resources, writing–review and editing. J.M.S.: Resources, writing–review and editing. A.S.: Resources, writing–review and editing. A.J.S.: Resources, writing–review and editing. I.V.: Resources, writing–review and editing. A.H.W.: Resources, writing–review and editing. J.D.B.: Resources, writing–review and editing. P.D.P.P.: Resources, writing–review and editing. C.L.P.: Resources, writing–review and editing. M.C.P.: Resources, writing–review and editing. E.L.G.: Resources, writing–review and editing. S.J.R.: Conceptualization, resources, data curation, supervision, funding acquisition, validation, writing–original draft, project administration, writing–review and editing. M.K.: Conceptualization, resources, data curation, investigation, formal analysis, validation, visualization, supervision, methodology, writing–original draft, writing–review and editing. B.N.: Resources, data curation, investigation, formal analysis, validation, visualization, methodology, writing–review and editing. A.DF.: Conceptualization, Resources, writing–review and editing. M.L.F.: Conceptualization, Resources, writing–review and editing. D.D.L.B.: Conceptualization, resources, supervision, funding acquisition, writing–original draft, writing–review and editing. D.W.G.: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing.

Corresponding authors

Correspondence to Tibor A. Zwimpfer or Dale W. Garsed.

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Competing interests

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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  • Received: 22 September 2025

  • Accepted: 13 March 2026

  • Published: 01 April 2026

  • DOI: https://doi.org/10.1038/s41467-026-71134-3

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