Orsulic, Sandra
Mayo Clinic
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
Citations 2
Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma
Saner, Flurina A.M. , Takahashi, Kazuaki , Budden, Timothy , Pandey, Ahwan , Ariyaratne, Dinuka , Zwimpfer, Tibor A. , Meagher, Nicola S. , Twomey, Laura , Hoang, Therese, Group, for the Australian Ovarian Cancer Study, Christie, Elizabeth L. , Kang, Eun-Young , Nelson, Gregg , Riggan, Marjorie J. , Alsop, Jennifer , Beckmann, Matthias W. , Boros, Jessica , Brand, Alison H. , Carney, Michael E. , Coulson, Penny , Courtney‐Brooks, Madeleine , Cushing‐Haugen, Kara L. , El‐Bahrawy, Mona , Gayther, Simon A. , Hartmann, Arndt , Hendley, Joy , Jimenez-Linan, Mercedes , Jones, Michael E. , Kluz, Tomasz , Koziak, Jennifer M. , Kristjansdottir, Björg , Le, Nhu D. , Lener, Marcin , Lester, Jenny , Mateoiu, Constantina , Oršulić, Sandra , Ruebner, Matthias , Schoemaker, Minouk J. , Shah, Mitul , Sharma, Raghwa , Shvetsov, Yurii B. , Soong, T. Rinda , Sukumvanich, Paniti , Talhouk, Aline , Anglesio, Michael S. , Fasching, Peter A. , Goodman, Marc T. , Huntsman, David G. , Kelemen, Linda E. , Menon, Usha , Pharoah, Paul D.P. , Schildkraut, Joellen M. , Goode, Ellen L. , Ramus, Susan J. , Bowtell, David D.L. , Garsed, Dale W. , Fereday, Sian , Twomey, Laura , Pishas, Kathleen I , Hoang, Therese , Bolithon, Adelyn , Traficante, Nadia , Alsop, Kathryn , Christie, Elizabeth L , Kang, Eun-Young , Nelson, Gregg S , Ghatage, Prafull , Lee, Cheng-Han , Riggan, Marjorie J , Alsop, Jennifer , Beckmann, Matthias W. , Boros, Jessica , Brand, Alison H , Brooks-Wilson, Angela R , Carney, Michael E , Coulson, Penny , Courtney-Brooks, Madeleine , Cushing-Haugen, Kara L , Cybulski, Cezary , El-Bahrawy, Mona A , Elishaev, Esther , Erber, Ramona , Gayther, Simon A , Gentry‐Maharaj, Aleksandra , Gilks, C. Blake , Harnett, Paul R , Harris, Holly R , Hartmann, Arndt , Hein, Alexander , Hendley, Joy , Hernandez, Brenda Y , Jakubowska, Anna , Jimenez-Linan, Mercedes , Jones, Michael E , Kaufmann, Scott H , Kennedy, Catherine J , Kluz, Tomasz , Koziak, Jennifer M , Kristjansdottir, Björg , Le, Nhu D , Lener, Marcin , Lester, Jenny , Lubinski, Jan , Mateoiu, Constantina , Orsulic, Sandra , Ruebner, Matthias , Schoemaker, Minouk J , Shah, Mitul , Sharma, Raghwa , Sherman, Mark E , Shvetsov, Yurii B , Soong, T Rinda , Steed, Helen , Sukumvanich, Paniti , Talhouk, Aline , Taylor, Sarah E , Vierkant, Robert A , Wang, Chen , Widschwendter, Martin , Wilkens, Lynne R , Winham, Stacey J , Anglesio, Michael S , Berchuck, Andrew , Brenton, James D , Campbell, Ian G , Cook, Linda S. , Doherty, Jennifer A , Fasching, Peter A , Fortner, Renée T , Goodman, Marc T , Gronwald, Jacek , Huntsman, David G , Karlan, Beth Y , Kelemen, Linda E , Menon, Usha , Modugno, Francesmary , Pharoah, Paul D P , Schildkraut, Joellen M , Sundfeldt, Karin , Swerdlow, Anthony J , Goode, Ellen L , Fazio, Anna de , Köbel, Martin , Ramus, Susan J , Bowtell, David D , Garsed, Dale W , Ariyaratne, Dinuka , Pandey, Ahwan , Fereday, Sián , Traficante, Nadia , Group, for the Australian Ovarian Cancer Study, Alsop, Kathryn , Lee, Cheng‐Han , Brooks‐Wilson, Angela , Cybulski, Cezary , Elishaev, Esther , Harnett, Paul R. , Harris, Holly R. , Hein, Alexander , Hernandez, Brenda Y. , Jakubowska, Anna , Kaufmann, Scott H. , Kennedy, Catherine J. , Lubiński, Jan , Sherman, Mark E. , Steed, Helen , Vierkant, Robert A. , Wang, Chen , Widschwendter, Martin , Wilkens, Lynne R. , Winham, Stacey J. , Berchuck, Andrew , Brenton, James D. , Campbell, Ian , Doherty, Jennifer A. , Fortner, Renée T. , Gronwald, Jacek , Karlan, Beth Y. , Modugno, Francesmary , Swerdlow, Anthony J. , DeFazio, Anna , Köbel, Martin
Clinical Cancer Research | June 5, 2024 | Volume: 30 | Issue: 16 | Pages: 3481-3498
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.
Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers
Glubb, Dylan M. , Thompson, Deborah J. , Aben, Katja K.H. , Alsulimani, Ahmad , Amant, Frédéric , Annibali, Daniela , Barricarte, Aurelio , Beckmann, Matthias W. , Bermisheva, Marina , Bernardini, Marcus Q. , Bischof, Katharina , Bodelón, Clara , Brand, Alison H. , Brinton, Louise A. , Bruinsma, Fiona , Burghaus, Stefanie , Cai, Hui , Carney, Michael E. , Chen, Chu , Chen, Xiao Qing, Chen, Zhihua , Cunningham, Julie M. , Vivo, Immaculata De , Dörk, Thilo , Edwards, Todd, Ekici, Arif B. , Ewing, Ailith , Fasching, Peter A. , Ferguson, Sarah, Flanagan, James M. , Fostira, Florentia, Gao, Bo , Gaudet, Mia M. , Gawełko, Jan , Goodman, Marc T. , Harter, Philipp , Hein, Alexander , Hildebrandt, Michelle A.T., Hillemanns, Peter , Høgdall, Claus , Holliday, Elizabeth , Huntsman, David G. , Huzarski, Tomasz , Jones, Michael E. , Kelley, Joseph L., Killeen, Jeffrey , Klapdor, Rüdiger , Köbel, Martin , Konopka, Bożena , Konstantopoulou, Irene , Kopperud, Reidun Kristin, Koti, Madhuri , Lambrechts, Diether , Lele, Shashikant , Lester, Jenny, Li, Andrew J., Liang, Dong , Liebrich, Clemens, Lipworth, Loren , Lissowska, Jolanta , Lu, Karen H., May, Taymaa, McGuire, Valerie , McNeish, Iain A. , Menon, Usha , Moysich, Kirsten B. , Odunsi, Kunle , Olsson, Håkan , Oršulić, Sandra , Osório, Ana , Park‐Simon, Tjoung‐Won , Pearce, Celeste Leigh, Podgórska, Agnieszka , Ramus, Susan J. , Riggan, Marjorie J. , Rothstein, Joseph H. , Runnebaum, Ingo B. , Scott, Rodney J. , Sellers, Thomas A. , Sieh, Weiva , Śpiewankiewicz, Beata, Sutphen, Rebecca , Teo, Soo‐Hwang , Thompson, Pamela J., Titus, Linda , Tone, Alicia , Edwards, Digna Velez, Vergote, Ignace , Wang, Zhaoming , Wang‐Gohrke, Shan , Group, for the OPAL Study, Group, for the AOCS, Whittemore, Alice S. , Wu, Xifeng , Wu, Anna H. , O’Mara, Tracy A. , Lu, Karen H. , Lambrechts, Diether , Barricarte, Aurelio , Bischof, Katharina , Bodelon, Clara , Brenton, James D , Brinton, Louise A , Buchanan, Daniel D , Cunningham, Julie M , De Vivo, Immaculata , Fazio, Anna de , Doherty, Jennifer A , Dörk, Thilo , Dunning, Alison M , Edwards, Todd , Ewing, Ailith , Fasching, Peter A , Flanagan, James M , Friedenreich, Christine M , Gaudet, Mia M , Gawełko, Jan , Gentry‐Maharaj, Aleksandra , Giles, Graham G , Glasspool, Rosalind , Harris, Holly R , Hein, Alexander , Heitz, Florian , Hillemanns, Peter , Jakubowska, Anna , Jones, Michael E , Karlan, Beth Y , Karnezis, Anthony , Kjaer, Susanne K , Klapdor, Rüdiger , Köbel, Martin , Konstantopoulou, Irene , Kupryjanczyk, Jolanta , Lambrechts, Diether , Lissowska, Jolanta , Lu, Lingeng , McAlpine, Jessica N , McNeish, Iain A , Menon, Usha , Nevanlinna, H , Orsulic, Sandra , Palli, Domenico , Park-Simon, Tjoung-Won , Permuth, Jennifer B , Ramus, Susan J , Runnebaum, Ingo B , Sieh, Weiva , Swerdlow, Anthony J , Szafron, Lukasz M , Teo, Soo H , Thompson, Pamela J , Thomsen, Liv Cecilie Vestrheim , Titus, Linda , Tumino, Rosario , Vanderstichele, Adriaan , Vergote, Ignace , Vierkant, Robert A , Webb, Penelope M , Winham, Stacey J , Spurdle, Amanda B , Lambrechts, Diether , Moysich, Kirsten , Wang, Zhaoming , O'Mara, Tracy A , Ekici, Arif B , Amant, Frederic , Høgdall, Claus K , Huzarski, Tomasz , Brand, Alison H , Goodman, Marc T , Attia, John , Berchuck, Andrew , Bjørge, Line , Brenton, James D. , Buchanan, Daniel D. , Bützow, Ralf C. , Chanock, Stephen Jacob , Chen, Xiao Qing, Cook, Linda S. , DeFazio, Anna , Doherty, Jennifer A. , Bois, Andreas du , Dunning, Alison M. , Dürst, Matthias , Fountzilas, George , Giles, Graham G. , Glasspool, Rosalind , Gronwald, Jacek , Harris, Holly R. , Heitz, Florian , Hildebrandt, Michelle A.T. , Høgdall, Estrid , Jakubowska, Anna , Jensen, Allan , Karlan, Beth Y. , Karnezis, Anthony N. , Хуснутдинова, Э. К. , Kjær, Susanne K. , Kraft, Peter , Kupryjańczyk, Jolanta , Larson, Melissa C. , Marchand, Loı̈c Le , Macciotta, Alessandra , Mattiello, Amalia , McAlpine, Jessica N. , Modugno, Francesmary , Nevanlinna, Heli , Palli, Domenico , Pejovic, Tanja B. , Permuth, Jennifer B. , Rebbeck, Timothy R. , Risch, Harvey A. , Senz, Janine , Setiawan, Veronica Wendy , Siddiqui, Nadeem , Swerdlow, Anthony J. , Szafron, Lukasz M. , Thomsen, Liv Cecilie Vestrheim , Tumino, Rosario , Turman, Constance , Vanderstichele, Adriaan , Edwards, Digna R. Velez , Vierkant, Robert A. , Webb, Penelope M. , Group, for the OPAL Study, Group, for the AOCS, White, Emily , Winham, Stacey J. , Yannoukakos, Drakoulis , Spurdle, Amanda B.
Cancer Epidemiology, Biomarkers & Prevention | November 3, 2020 | Volume: 30 | Issue: 1 | Pages: 217-228
Abstract Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni < 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P < 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.