Concurrent RB1 Loss and <i>BRCA</i> Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Flurina A.M. Saner, Kazuaki Takahashi, Timothy Budden, Ahwan Pandey, Dinuka Ariyaratne, Tibor A. Zwimpfer, Nicola S. Meagher, Sián Fereday, Laura Twomey, Kathleen I. Pishas, Therese Hoang, Adelyn Bolithon, Nadia Traficante, for the Australian Ovarian Cancer Study Group, Kathryn Alsop, Elizabeth L. Christie, Eun-Young Kang, Gregg Nelson, Prafull Ghatage, Cheng‐Han Lee, Marjorie J. Riggan, Jennifer Alsop, Matthias W. Beckmann, Jessica Boros, Alison H. Brand, Angela Brooks‐Wilson, Michael E. Carney, Penny Coulson, Madeleine Courtney‐Brooks, Kara L. Cushing‐Haugen, Cezary Cybulski, Mona El‐Bahrawy, Esther Elishaev, Ramona Erber, Simon A. Gayther, Aleksandra Gentry‐Maharaj, C. Blake Gilks, Paul R. Harnett, Holly R. Harris, Arndt Hartmann, Alexander Hein, Joy Hendley, Brenda Y. Hernandez, Anna Jakubowska, Mercedes Jimenez-Linan, Michael E. Jones, Scott H. Kaufmann, Catherine J. Kennedy, Tomasz Kluz, Jennifer M. Koziak, Björg Kristjansdottir, Nhu D. Le, Marcin Lener, Jenny Lester, Jan Lubiński, Constantina Mateoiu, Sandra Oršulić, Matthias Ruebner, Minouk J. Schoemaker, Mitul Shah, Raghwa Sharma, Mark E. Sherman, Yurii B. Shvetsov, T. Rinda Soong, Helen Steed, Paniti Sukumvanich, Aline Talhouk, Sarah E. Taylor, Robert A. Vierkant, Chen Wang, Martin Widschwendter, Lynne R. Wilkens, Stacey J. Winham, Michael S. Anglesio, Andrew Berchuck, James D. Brenton, Ian Campbell, Linda S. Cook, Jennifer A. Doherty, Peter A. Fasching, Renée T. Fortner, Marc T. Goodman, Jacek Gronwald, David G. Huntsman, Beth Y. Karlan, Linda E. Kelemen, Usha Menon, Francesmary Modugno, Paul D.P. Pharoah, Joellen M. Schildkraut, Karin Sundfeldt, Anthony J. Swerdlow, Ellen L. Goode, Anna DeFazio, Martin Köbel, Susan J. Ramus, David D.L. Bowtell, Dale W. Garsed
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.