PubMed · 41040691
Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.
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 unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.
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Tibor A Zwimpfer, Sian Fereday, Ahwan Pandey, Dinuka Ariyaratne, Madawa W Jayawardana, Laura Twomey, Céline M Laumont, Catherine J Kennedy, Adelyn Bolithon, Nicola S Meagher, Katy Milne, Phineas Hamilton, Jennifer Alsop, Antonis C Antoniou, George Au-Yeung, Matthias W Beckmann, Amy Berrington de Gonzalez, Christiani Bisinotto, Freya Blome, Clara Bodelon, Jessica Boros, Alison H Brand, Michael E Carney, Alicia Cazorla-Jiménez, Derek S Chiu, Elizabeth L Christie, Anita Chudecka-Głaz, Penny Coulson, Kara L Cushing-Haugen, Cezary Cybulski, Kathleen M Darcy, Cath David, Trent Davidson, Arif B Ekici, Esther Elishaev, Julius Emons, Tobias Engler, Rhonda Farrell, Anna Fischer, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Prafull Ghatage, Rosalind Glasspool, Philipp Harter, Andreas D Hartkopf, Arndt Hartmann, Sebastian Heikaus, Brenda Y Hernandez, Anusha Hettiaratchi, Sabine Heublein, David G Huntsman, Mercedes Jimenez-Linan, Michael E Jones, Eunyoung Kang, Ewa Kaznowska, Tomasz Kluz, Felix K F Kommoss, Gottfried Konecny, Roy F P M Kruitwagen, Jessica Kwon, Diether Lambrechts, Cheng-Han Lee, Jenny Lester, Samuel C Y Leung, Yee Leung, Anna Linder, Jolanta Lissowska, Liselore Loverix, Jan Lubiński, Constantina Mateoiu, Iain A McNeish, Malak Moubarak, Gregg S Nelson, Nikilyn Nevins, Alexander B Olawaiye, Siel Olbrecht, Sandra Orsulic, Ana Osorio, Carmel M Quinn, Ganendra Raj Mohan, Isabelle Ray-Coquard, Cristina Rodríguez-Antona, Patricia Roxburgh, Matthias Ruebner, Stuart G Salfinger, Spinder Samra, Minouk J Schoemaker, Hans-Peter Sinn, Gabe S Sonke, Linda Steele, Colin J R Stewart, Aline Talhouk, Adeline Tan, Christopher M Tarney, Sarah E Taylor, Koen K Van de Vijver, Maaike A van der Aa, Toon Van Gorp, Els Van Nieuwenhuysen, Lilian van-Wagensveld. 2025-09-22. Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.. https://doi.org/10.1101/2025.09.17.25335919
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