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

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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Journal
Nature Communications
Published
2026-04-01
DOI
https://doi.org/10.1038/s41467-026-71134-3
Primary Topic
PARP inhibition in cancer therapy
Type
article
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0.00

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article

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

Jolanta Lissowska, Stuart Salfinger, Jennifer Alsop, Nicola S. Meagher et al.
Nature Communications
PARP inhibition in cancer therapy
article

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

Jolanta Lissowska, Stuart Salfinger, Jennifer Alsop, Nicola S. Meagher, Constantina Mateoiu, Minouk J. Schoemaker, Derek S. Chiu, Roy F.P.M. Kruitwagen, Ewa Kaznowska, Felix K. F. Kommoss, Brenda Hernandez, Anusha Hettiaratchi, Koen Van de Vijver, Esther Elishaev, Penny Coulson, Liselore Loverix, Adelyn Bolithon, Nikilyn Nevins, Christiani Bisinotto, Anna Linder, A. Olawaiye, Sebastian Heikaus, Jessica J Kwon, Carmel M. Quinn, Christopher M. Tarney, M Ruebner, Sabine Heublein, P. Ghatage, Samuel Leung, Arif B. Ekici, Spinder Samra, Catherine J. Kennedy, Patricia Roxburgh, Phineas T. Hamilton, Amy Berrington de González, Anna Fischer, Alicia Cazorla, Sián Fereday, A Hartmann, Tobias Engler, AD Hartkopf, Adeline Tan, Madawa Jayawardana, Gottfried E. Konecny, Jessica Boros, Katy Milne, Céline M. Laumont, Ahwan Pandey, Sandra Oršulić, Tibor A. Zwimpfer, Alison H. Brand, Yee Leung, Siel Olbrecht, Toon Van Gorp, Aline Talhouk, M. Jimenez-Linan, Malak Moubarak Moubarak, Julius Emons, Cezary Cybulski, Iain A. McNeish, Tomasz Kluz, Dinuka Ariyaratne, Freya Blome, Laura Twomey, Kara L. Cushing-Haugen, G. Raj K. A. Mohan, Cristina Rodriguez-Antona, Hans-Peter Sinn, Montserrat Garcia-Closas, George Au-Yeung, E. Kang, G. Nelson, Kathleen M. Darcy, Sarah E. Taylor, Rosalind Glasspool, Ana Osorio, Colin J. R. Stewart, David G. Huntsman, Lilian Van-Wagensveld, Michael E. Carney, Rhonda Farrell, Matthias W. Beckmann, Aleksandra Gentry-Maharaj, Jenny Lester, Philipp Harter, Diether Lambrechts, Michael E. Jones, Cheng-Han Lee, Els Van Nieuwenhuysen, Anita Chudecka-Głaz, Maaike A. van der Aa, Isabelle Ray-Coquard, Cath David, Linda Steele, Trent Davidson, Elizabeth L. Christie, Clara Bodelon, Jan Lubiński, Gabe S. Sonke
article en

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.

Nature Communications
Université Claude Bernard Lyon 1 (FR), University of Hawaiʻi at Mānoa (US), Henry M. Jackson Foundation (US), American Cancer Society (US), St John of God Subiaco Hospital (AU), The University of Sydney (AU), New South Wales Department of Health (AU), University of Hawaii System (US), University of British Columbia (CA), Institute of Cancer Research (GB), University of Alberta (CA), University of California, Los Angeles (US), The University of Melbourne (AU), University of Calgary (CA), University of Pittsburgh (US), The University of Western Australia (AU), Universidade de São Paulo (BR), Heidelberg University (DE), University of Cambridge (GB), Royal Hospital for Women (AU), Maastricht University Medical Centre (NL), Walter Reed National Military Medical Center (US), Beatson West of Scotland Cancer Centre (GB), Peter MacCallum Cancer Centre (AU), King Edward Memorial Hospital (AU), Cancer Institute of New South Wales (AU), University Hospital Heidelberg (DE), University Hospital of Basel (CH), Vancouver General Hospital (CA), Westmead Hospital (AU), Seoul National University Bundang Hospital (KR), The Netherlands Cancer Institute (NL), UNSW Sydney (AU), Maastricht University (NL), Cancer Australia (AU), Universitätsklinikum Erlangen (DE), Fred Hutch Cancer Center (US), MRC Clinical Trials Unit at UCL (GB), Instituto de Investigaciones Biomédicas Sols-Morreale (ES), VIB-KU Leuven Center for Cancer Biology (BE), Cancer Center of Hawaii (US), Ovarian Cancer Action (GB), Antwerp University Hospital (BE), Centre Léon Bérard (FR), Prince of Wales Hospital (AU), City of Hope (US), Centre for Biomedical Network Research on Rare Diseases (ES), Cancer Research Institute Ghent (BE), National Institute of Oncology (HU), St Vincent's Clinic (AU), Department of Biomedicine Basel (CH), Hospital Universitario Fundación Jiménez Díaz (ES), Sonic Healthcare (Germany) (DE), Netherlands Comprehensive Cancer Organisation (NL), Westmead Institute for Medical Research (AU), Kliniken Essen-Mitte (DE), Comprehensive Cancer Center Erlangen (DE), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), University Hospital Ulm (DE), Addenbrooke's Hospital (GB), Maastro Clinic (NL), Beckman Research Institute, University of Hawaii Cancer Center, University College London (GB), Imperial College London (GB), Western Sydney University (AU), Universidad Autónoma de Madrid (ES), University of Glasgow (GB), Pomeranian Medical University (PL), University of Tübingen (DE), University of Gothenburg (SE), Cancer Council NSW (AU), University of Rzeszów (PL), Mississippi State University (US), KU Leuven (BE)
Victorian Cancer Agency, Breast Cancer Now, Ovarian Cancer Research Foundation, Peter MacCallum Cancer Centre, Gottfried und Julia Bangerter-Rhyner-Stiftung, Medizinische Abteilung der Margarete und Walter Lichtenstein-Stiftung, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, Medical Research and Materiel Command
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PARP inhibition in cancer therapy
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