| Title: |
Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA -deficient tubo-ovarian high-grade serous carcinoma |
| Authors: |
Zwimpfer, Tibor; Fereday, Sian; Pandey, Ahwan; Ariyaratne, Dinuka; Jayawardana, Madawa; Twomey, Laura; Laumont, Céline; Kennedy, Catherine; Bolithon, Adelyn; Meagher, Nicola; Milne, Katy; Hamilton, Phineas; Alsop, Jennifer; Antoniou, Antonis; Au-Yeung, George; Beckmann, Matthias; Berrington de Gonzalez, Amy; Bisinotto, Christiani; Blome, Freya; Bodelon, Clara; Boros, Jessica; Brand, Alison; Carney, Michael; Cazorla-Jiménez, Alicia; Chiu, Derek; Christie, Elizabeth; Chudecka-Głaz, Anita; Coulson, Penny; Cushing-Haugen, Kara; Cybulski, Cezary; Darcy, Kathleen; David, Cath; Davidson, Trent; Ekici, Arif; Elishaev, Esther; Emons, Julius; Engler, Tobias; Farrell, Rhonda; Fischer, Anna; García-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Ghatage, Prafull; Glasspool, Rosalind; Harter, Philipp; Hartkopf, Andreas; Hartmann, Arndt; Heikaus, Sebastian; Hernandez, Brenda; Hettiaratchi, Anusha; Heublein, Sabine; Huntsman, David; Jimenez-Linan, Mercedes; Jones, Michael; Kang, Eunyoung; Kaznowska, Ewa; Kluz, Tomasz; Kommoss, Felix; Konecny, Gottfried; Kruitwagen, Roy; Kwon, Jessica; Lambrechts, Diether; Lee, Cheng-Han; Lester, Jenny; Leung, Samuel; Leung, Yee; Linder, Anna; Lissowska, Jolanta; Loverix, Liselore; Lubiński, Jan; Mateoiu, Constantina; Mcneish, Iain; Moubarak, Malak; Nelson, Gregg; Nevins, Nikilyn; Olawaiye, Alexander; Olbrecht, Siel; Orsulic, Sandra; Osorio, Ana; Quinn, Carmel; Raj Mohan, Ganendra; Ray-Coquard, Isabelle; Rodríguez-Antona, Cristina; Roxburgh, Patricia; Ruebner, Matthias; Salfinger, Stuart; Samra, Spinder; Schoemaker, Minouk; Sinn, Hans-Peter; Sonke, Gabe; Steele, Linda; Stewart, Colin; Talhouk, Aline; Tan, Adeline; Tarney, Christopher; Taylor, Sarah; van de Vijver, Koen; van der Aa, Maaike; van Gorp, Toon; van Nieuwenhuysen, Els; Van-Wagensveld, Lilian; Wahner-Hendrickson, Andrea; Walter, Christina; Wang, Chen; Welz, Julia; Wentzensen, Nicolas; Wilkens, Lynne; Winham, Stacey; Winterhoff, Boris; Anglesio, Michael; Berchuck, Andrew; Candido dos Reis, Francisco; Cohen, Paul; Conrads, Thomas; Crowe, Philip; Doherty, Jennifer; Fasching, Peter; Fortner, Renée; García, María; Gayther, Simon; Goodman, Marc; Gronwald, Jacek; Harris, Holly; Heitz, Florian; Horlings, Hugo; Karlan, Beth; Kelemen, Linda; Maxwell, G Larry; Menon, Usha; Modugno, Francesmary; Neuhausen, Susan; Schildkraut, Joellen; Staebler, Annette; Sundfeldt, Karin; Swerdlow, Anthony; Vergote, Ignace; Wu, Anna; Brenton, James; Pharoah, Paul; Pearce, Celeste Leigh; Pike, Malcolm; Goode, Ellen; Ramus, Susan; Köbel, Martin; Nelson, Brad; Defazio, Anna; Friedlander, Michael; Bowtell, David; Garsed, Dale; Kommoss, Felix K.F.; Kruitwagen, Roy F.P.M.; Leung, Samuel C.Y.; Stewart, Colin J.R.; Maxwell, G. Larry; Pharoah, Paul D.P.; Bowtell, David D.L. |
| Contributors: |
Research on Healthcare Performance (RESHAPE - Inserm U1290 - UCBL1); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Source: |
Medrxiv : the Preprint Server For Health Sciences ; https://univ-lyon1.hal.science/hal-05353842 ; Medrxiv : the Preprint Server For Health Sciences, 2025, ⟨10.1101/2025.09.17.25335919⟩ |
| Publisher Information: |
CCSD |
| Publication Year: |
2025 |
| Collection: |
HAL Lyon 1 (University Claude Bernard Lyon 1) |
| Subject Terms: |
[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie |
| Description: |
International audience ; 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 (g BRCA pv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in g BRCA pv-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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/41040691; MEDRXIV: 2025.09.17.25335919; PUBMED: 41040691; PUBMEDCENTRAL: PMC12486008 |
| DOI: |
10.1101/2025.09.17.25335919 |
| Availability: |
https://univ-lyon1.hal.science/hal-05353842; https://doi.org/10.1101/2025.09.17.25335919 |
| Accession Number: |
edsbas.DFE88FC2 |
| Database: |
BASE |