Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma
- Author(s)
- 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, MW; 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, FKF; Konecny, G; Kruitwagen, RFPM; Kwon, J; Lambrechts, D; Lee, CH; Lester, J; Leung, SCY; 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; Ruebner, M; Salfinger, SG; Samra, S; Schoemaker, MJ; Sinn, HP; Sonke, GS; Steele, L; Stewart, CJR; 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, PA; 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, PDP; Pearce, CL; Pike, MC; Goode, EL; Ramus, SJ; Köbel, M; Nelson, BH; DeFazio, A; Friedlander, ML; Bowtell, DDL; Garsed, DW;
- Journal Title
- Nature Communications
- Publication Type
- Online publication before print
- 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.
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41467-026-71134-3
- Open Access at Publisher's Site
https://doi.org/10.1038/s41467-026-71134-3- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-04-14 03:18:27
Last Modified: 2026-04-14 03:18:35