| Title: |
Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma. |
| Authors: |
Zwimpfer, Tibor A; Fereday, Sian; Pandey, Ahwan; Ariyaratne, Dinuka; Jayawardana, Madawa W; Twomey, Laura; Laumont, Céline M; Kennedy, Catherine J; Bolithon, Adelyn; Meagher, Nicola S; Milne, Katy; Hamilton, Phineas; Alsop, Jennifer; Antoniou, Antonis C; Au-Yeung, George; Beckmann, Matthias W; Berrington de Gonzalez, Amy; Bisinotto, Christiani; Blome, Freya; Bodelon, Clara; Boros, Jessica; Brand, Alison H; Carney, Michael E; Cazorla-Jiménez, Alicia; Chiu, Derek S; Christie, Elizabeth L; Chudecka-Głaz, Anita; Coulson, Penny; Cushing-Haugen, Kara L; Cybulski, Cezary; Darcy, Kathleen M; David, Cath; Davidson, Trent; Ekici, Arif B; Elishaev, Esther; Emons, Julius; Engler, Tobias; Farrell, Rhonda; Fischer, Anna; García-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghatage, Prafull; Glasspool, Rosalind; Harter, Philipp; Hartkopf, Andreas D; Hartmann, Arndt; Heikaus, Sebastian; Hernandez, Brenda Y; Hettiaratchi, Anusha; Heublein, Sabine; Huntsman, David G; Jimenez-Linan, Mercedes; Jones, Michael E; Kang, Eunyoung; Kaznowska, Ewa; Kluz, Tomasz; Kommoss, Felix KF; Konecny, Gottfried; Kruitwagen, Roy FPM; Kwon, Jessica; Lambrechts, Diether; Lee, Cheng-Han; Lester, Jenny; Leung, Samuel CY; Leung, Yee; Linder, Anna; Lissowska, Jolanta; Loverix, Liselore; Lubiński, Jan; Mateoiu, Constantina; McNeish, Iain A; Moubarak, Malak; Nelson, Gregg S; Nevins, Nikilyn; Olawaiye, Alexander B; Olbrecht, Siel; Orsulic, Sandra; Osorio, Ana; Quinn, Carmel M; Mohan, Ganendra Raj; Ray-Coquard, Isabelle; Rodríguez-Antona, Cristina; Roxburgh, Patricia; Ruebner, Matthias; Salfinger, Stuart G; Samra, Spinder; Schoemaker, Minouk J; Sinn, Hans-Peter; Sonke, Gabe S; Steele, Linda; Stewart, Colin JR; Talhouk, Aline; Tan, Adeline; Tarney, Christopher M; Taylor, Sarah E; Van de Vijver, Koen K; van der Aa, Maaike A; Van Gorp, Toon; Van Nieuwenhuysen, Els; Van-Wagensveld, Lilian; Wahner-Hendrickson, Andrea E; Walter, Christina; Wang, Chen; Welz, Julia; Wentzensen, Nicolas; Wilkens, Lynne R; Winham, Stacey J; Winterhoff, Boris; Anglesio, Michael S; Berchuck, Andrew; Candido Dos Reis, Francisco J; Cohen, Paul A; Conrads, Thomas P; Crowe, Philip; Doherty, Jennifer A; Fasching, Peter A; Fortner, Renée T; García, María J; Gayther, Simon A; Goodman, Marc T; Gronwald, Jacek; Harris, Holly R; Heitz, Florian; Horlings, Hugo M; Karlan, Beth Y; Kelemen, Linda E; Larry Maxwell, G; Menon, Usha; Modugno, Francesmary; Neuhausen, Susan L; Schildkraut, Joellen M; Staebler, Annette; Sundfeldt, Karin; Swerdlow, Anthony J; Vergote, Ignace; Wu, Anna H; Brenton, James D; Pharoah, Paul DP; Pearce, Celeste Leigh; Pike, Malcolm C; Goode, Ellen L; Ramus, Susan J; Köbel, Martin; Nelson, Brad H; DeFazio, Anna; Friedlander, Michael L; Bowtell, David DL; Garsed, Dale W |
| Publisher Information: |
Springer Nature; Department of Public Health and Primary Care, Cancer Genetic Epidemiology; //doi.org/10.1038/s41467-026-71134-3 |
| Publication Year: |
2026 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
31 Biological Sciences |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://www.repository.cam.ac.uk/handle/1810/400369; https://doi.org/10.17863/CAM.128568 |
| DOI: |
10.17863/CAM.128568 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/400369; https://doi.org/10.17863/CAM.128568 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.EBFC28AA |
| Database: |
BASE |