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

Zwimpfer TA, Fereday S, Pandey A, Ariyaratne D, Jayawardana MW, Twomey L, Laumont CM, Kennedy CJ, Bolithon A, Meagher NS, Milne K, Hamilton P, Alsop J, Antoniou AC, Au-Yeung G, Beckmann M, Berrington de Gonzalez A, Bisinotto C, Blome F, Bodelon C, Boros J, Brand AH, Carney ME, Cazorla-Jiménez A, Chiu DS, Christie EL, Chudecka-Głaz A, Coulson P, Cushing-Haugen KL, Cybulski C, Darcy KM, David C, Davidson T, Ekici AB, Elishaev E, Emons J, Engler T, Farrell R, Fischer A, García-Closas M, Gentry-Maharaj A, Ghatage P, Glasspool R, Harter P, Hartkopf AD, Hartmann A, Heikaus S, Hernandez BY, Hettiaratchi A, Heublein S, Huntsman DG, Jimenez-Linan M, Jones ME, Kang E, Kaznowska E, Kluz T, Kommoss FK, Konecny G, Kruitwagen RF, Kwon J, Lambrechts D, Lee CH, Lester J, Leung SC, Leung Y, Linder A, Lissowska J, Loverix L, Lubiński J, Mateoiu C, McNeish IA, Moubarak M, Nelson GS, Nevins N, Olawaiye AB, Olbrecht S, Orsulic S, Osorio A, Quinn CM, Mohan GR, Ray-Coquard I, Rodríguez-Antona C, Roxburgh P, Rübner M, Salfinger SG, Samra S, Schoemaker MJ, Sinn HP, Sonke GS, Steele L, Stewart CJ, Talhouk A, Tan A, Tarney CM, Taylor SE, Van de Vijver KK, van der Aa MA, Van Gorp T, Van Nieuwenhuysen E, Van-Wagensveld L, Wahner-Hendrickson AE, Walter C, Wang C, Welz J, Wentzensen N, Wilkens LR, Winham SJ, Winterhoff B, Anglesio MS, Berchuck A, Candido dos Reis FJ, Cohen PA, Conrads TP, Crowe P, Doherty JA, Fasching P, Fortner RT, García MJ, Gayther SA, Goodman MT, Gronwald J, Harris HR, Heitz F, Horlings HM, Karlan BY, Kelemen LE, Larry Maxwell G, Menon U, Modugno F, Neuhausen SL, Schildkraut JM, Staebler A, Sundfeldt K, Swerdlow AJ, Vergote I, Wu AH, Brenton JD, Pharoah PD, Pearce CL, Pike MC, Goode EL, Ramus SJ, Köbel M, Nelson BH, DeFazio A, Friedlander ML, Bowtell DD, Garsed DW (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 17

Article Number: 4789

Journal Issue: 1

DOI: 10.1038/s41467-026-71134-3

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.

Authors with CRIS profile

Involved external institutions

University of California Los Angeles (UCLA) United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Instituto de Investigaciones Biomédicas Alberto Sols (IIBM) Spain (ES) University of Texas Health Science Center at San Antonio (UTHSCSA) United States (USA) (US) Mayo Clinic United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) University of British Columbia Canada (CA) Cedars-Sinai Medical Center United States (USA) (US) Duke University Medical Center United States (USA) (US) University of São Paulo / Universidade de São Paulo (USP) Brazil (BR) University of Western Australia (UWA) Australia (AU) Fred Hutchinson Cancer Research Center United States (USA) (US) Kliniken Essen-Mitte Germany (DE) King Edward Memorial Hospital Australia (AU) Uniformed Services University United States (USA) (US) University of New South Wales (UNSW) Australia (AU) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL) University College London (UCL) United Kingdom (GB) University of Pittsburgh United States (USA) (US) University of Cambridge United Kingdom (GB) Peter MacCallum Cancer Centre Australia (AU) The Institute of Cancer Research (ICR) United Kingdom (GB) Universitätsklinikum Tübingen Germany (DE) American Cancer Society United States (USA) (US) Westmead Institute for Medical Research Australia (AU) Westmead Hospital Australia (AU) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) University of Alberta Canada (CA) University of Hawaii (U.H.) United States (USA) (US) Maastricht University Netherlands (NL) Fundación Jiménez Díaz Spain (ES) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Mississippi State University for Agriculture and Applied Science United States (USA) (US) Royal Hospital for Women Australia (AU) Prince of Wales Hospital (POWH) Australia (AU) Seoul National University Bundang Hospital (SNUBH) / 분당 서울대병원 Korea, Republic of (KR) University of Calgary Canada (CA) University of Glasgow United Kingdom (GB) Universitätsklinikum Heidelberg Germany (DE) Addenbrooke's Hospital United Kingdom (GB) Uniwersytet Rzeszowski Poland (PL) British Columbia Cancer Agency Canada (CA) University Hospital Ghent Belgium (BE) Netherlands Comprehensive Cancer Organisation / Integraal Kankercentrum Nederland (IKNL) Netherlands (NL) University of Gothenburg / Göteborgs universitet Sweden (SE) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) City of Hope Medical Center United States (USA) (US) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) Hospital Universitario Fundación Jiménez Díaz Spain (ES) Université Claude Bernard Lyon 1 (UCB) France (FR) Ciber de Enfermedades Raras (CIBERER) Spain (ES) St John of God Health Care Australia (AU) Huntsman Cancer Institute United States (USA) (US) Emory University United States (USA) (US) Keck School of Medicine of USC United States (USA) (US) University of Michigan United States (USA) (US)

How to cite

APA:

Zwimpfer, T.A., Fereday, S., Pandey, A., Ariyaratne, D., Jayawardana, M.W., Twomey, L.,... Garsed, D.W. (2026). Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma. Nature Communications, 17(1). https://doi.org/10.1038/s41467-026-71134-3

MLA:

Zwimpfer, Tibor A., et al. "Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma." Nature Communications 17.1 (2026).

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