Clinicopathologic and molecular predictors of survival in 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 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:
- TA Zwimpfer, S Fereday, A Pandey, D Ariyaratne, MW Jayawardana, L Twomey, CM Laumont, CJ Kennedy, A Bolithon, NS Meagher, K Milne, P Hamilton, J Alsop, AC Antoniou, G Au-Yeung, MW Beckmann, A Berrington de Gonzalez, C Bisinotto, F Blome, C Bodelon, J Boros, AH Brand, ME Carney, A Cazorla-JimĂ©nez, DS Chiu, EL Christie, A Chudecka-GĹ‚az, P Coulson, KL Cushing-Haugen, C Cybulski, KM Darcy, C David, T Davidson, AB Ekici, E Elishaev, J Emons, T Engler, R Farrell, A Fischer, M GarcĂa-Closas, A Gentry-Maharaj, P Ghatage, R Glasspool, P Harter, AD Hartkopf, A Hartmann, S Heikaus, BY Hernandez, A Hettiaratchi, S Heublein, DG Huntsman, M Jimenez-Linan, ME Jones, E Kang, E Kaznowska, T Kluz, FKF Kommoss, G Konecny, RFPM Kruitwagen, J Kwon, D Lambrechts, C-H Lee, J Lester, SCY Leung, Y Leung, A Linder, J Lissowska, L Loverix, J LubiĹ„ski, C Mateoiu, IA McNeish, M Moubarak, GS Nelson, N Nevins, AB Olawaiye, S Olbrecht, S Orsulic, A Osorio, CM Quinn, GR Mohan, I Ray-Coquard, C RodrĂguez-Antona, P Roxburgh, M Ruebner, SG Salfinger, S Samra, MJ Schoemaker, H-P Sinn, GS Sonke, L Steele, CJR Stewart, A Talhouk, A Tan, CM Tarney, SE Taylor, KK Van de Vijver, MA van der Aa, T Van Gorp, E Van Nieuwenhuysen, L Van-Wagensveld, AE Wahner-Hendrickson, C Walter, C Wang, J Welz, N Wentzensen, LR Wilkens, SJ Winham, B Winterhoff, MS Anglesio, A Berchuck, FJ Candido Dos Reis, PA Cohen, TP Conrads, P Crowe, JA Doherty, PA Fasching, RT Fortner, MJ GarcĂa, SA Gayther, MT Goodman, J Gronwald, HR Harris, F Heitz, HM Horlings, BY Karlan, LE Kelemen, G Larry Maxwell, U Menon, F Modugno, SL Neuhausen, JM Schildkraut, A Staebler, K Sundfeldt, AJ Swerdlow, I Vergote, AH Wu, JD Brenton, PDP Pharoah, CL Pearce, MC Pike, EL Goode, SJ Ramus, M Köbel, BH Nelson, A DeFazio, ML Friedlander, DDL Bowtell, DW Garsed
- Journal:
- Nat Commun
- Publication date:
- 1st Apr 2026
- Full text
- DOI