Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Saner FA, Takahashi K, Budden T, Pandey A, Ariyaratne D, Zwimpfer TA, Meagher NS, Fereday S, Twomey L, Pishas KI, Hoang T, Bolithon A, Traficante N, Alsop K, Christie EL, Kang EY, Nelson GS, Ghatage P, Lee CH, Riggan MJ, Alsop J, Beckmann M, Boros J, Brand AH, Brooks-Wilson A, Carney ME, Coulson P, Courtney-Brooks M, Cushing-Haugen KL, Cybulski C, El-Bahrawy MA, Elishaev E, Erber R, Gayther SA, Gentry-Maharaj A, Gilks CB, Harnett PR, Harris HR, Hartmann A, Hein A, Hendley J, Hernandez BY, Jakubowska A, Jimenez-Linan M, Jones ME, Kaufmann SH, Kennedy CJ, Kluz T, Koziak JM, Kristjansdottir B, Le ND, Lener M, Lester J, Lubiński J, Mateoiu C, Orsulic S, Rübner M, Schoemaker MJ, Shah M, Sharma R, Sherman ME, Shvetsov YB, Soong TR, Steed H, Sukumvanich P, Talhouk A, Taylor SE, Vierkant RA, Wang C, Widschwendter M, Wilkens LR, Winham SJ, Anglesio MS, Berchuck A, Brenton JD, Campbell I, Cook LS, Doherty JA, Fasching P, Fortner RT, Goodman MT, Gronwald J, Huntsman DG, Karlan BY, Kelemen LE, Menon U, Modugno F, Pharoah PD, Schildkraut JM, Sundfeldt K, Swerdlow AJ, Goode EL, DeFazio A, Köbel M, Ramus SJ, Bowtell DD, Garsed DW (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 30

Pages Range: 3481-3498

Journal Issue: 16

DOI: 10.1158/1078-0432.CCR-23-3552

Abstract

PURPOSE: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. RESULTS: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. CONCLUSIONS: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Authors with CRIS profile

Involved external institutions

University of Sydney (USYD) Australia (AU) University of Calgary Canada (CA) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Peter MacCallum Cancer Centre Australia (AU) Mayo Clinic United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) University of British Columbia Canada (CA) University of California Los Angeles (UCLA) United States (USA) (US) South Carolina Department of Health and Environmental Control United States (USA) (US) University College London (UCL) United Kingdom (GB) University of Pittsburgh United States (USA) (US) University of Cambridge United Kingdom (GB) Emory University United States (USA) (US) British Columbia Cancer Agency Canada (CA) University of Alberta Canada (CA) University of New South Wales (UNSW) Australia (AU) Uniwersytet Rzeszowski Poland (PL) The Institute of Cancer Research (ICR) United Kingdom (GB) Fred Hutchinson Cancer Research Center United States (USA) (US) Alberta Health Services (AHS) Canada (CA) Leopold-Franzens-Universität Innsbruck / University of Innsbruck Austria (AT) Westmead Hospital Australia (AU) Duke University Medical Center United States (USA) (US) Mayo Clinic Hospital United States (USA) (US) University of Hawaii (U.H.) United States (USA) (US) Addenbrooke's Hospital United Kingdom (GB) Westmead Institute for Medical Research Australia (AU) University of Gothenburg / Göteborgs universitet Sweden (SE) University of Colorado Anschutz Medical Campus United States (USA) (US) University of Utah United States (USA) (US) Canada's Michael Smith Genome Sciences Centre Canada (CA) Hammersmith Hospital United Kingdom (GB)

How to cite

APA:

Saner, F.A., Takahashi, K., Budden, T., Pandey, A., Ariyaratne, D., Zwimpfer, T.A.,... Garsed, D.W. (2024). Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma. Clinical Cancer Research, 30(16), 3481-3498. https://doi.org/10.1158/1078-0432.CCR-23-3552

MLA:

Saner, Flurina A.M., et al. "Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma." Clinical Cancer Research 30.16 (2024): 3481-3498.

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