Citations 2
Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma
Garsed, Dale W. , Pandey, Ahwan , Ariyaratne, Dinuka , Laumont, Céline M. , Hamilton, Phineas T. , Alsop, Jennifer , Antoniou, Antonis C. , Au‐Yeung, George , Beckmann, Matthias W. , González, Amy Berrington de , Bisinotto, Christiani, Blome, Freya , Bodelón, Clara , Boros, Jessica , Brand, Alison H. , Carney, Michael E., Coulson, Penny , Cushing‐Haugen, Kara L. , Cybulski, Cezary, Darcy, Kathleen M. , David, C. W. Mabey, Davidson, Trent , Emons, Julius , Farrell, Rhonda , Gentry-Maharaj, Aleksandra, Harter, Philipp, Hartmann, Arndt, Heikaus, Sebastian, Hettiaratchi, Anusha , Heublein, Sabine , Huntsman, David G. , Jimenez-Linan, Mercedes , Jones, Michael E. , Kang, Eunyoung , Konecny, Gottfried E. , Kruitwagen, Rutgerus, Kwon, Jessica, Lambrechts, Diether , Lester, Jenny, Leung, Samuel , Leung, Yee , Loverix, Liselore , Mateoiu, Constantina , McNeish, Iain A. , Nevins, Nikilyn, Olawaiye, Alexander , Oršulić, Sandra , Osório, Ana , Quinn, Carmel M. , Mohan, Ganendra Raj , Ruebner, Matthias , Salfinger, Stuart , Samra, Spinder , Stewart, Colin J.R. , Talhouk, Aline , Tan, Adeline , Tarney, Christopher M., Aa, Maaike AVan Der, Gorp, Toon Van , Nieuwenhuysen, Els Van, Wagensveld, Lilian van , Wahner-Hendrickson, Andrea E., Walter, Christina B., Welz, Julia , Wentzensen, Nicolas , Winterhoff, Boris , Berchuck, Andrew, Fasching, Peter A. , Gayther, Simon A. , Kelemen, Linda E. , Maxwell, G. Larry , Menon, Usha , Modugno, Francesmary, Schildkraut, Joellen M. , Staebler, Annette , Swedlow, Anthony, Vergote, Ignace , Wu, Anna H. , Pearce, Celeste Leigh, Pike, M. C., Goode, Ellen L. , Bowtell, David D.L. , Lambrechts, Diether , Garsed, Dale W , Fereday, Sian , Pandey, Ahwan , Ariyaratne, Dinuka , Kennedy, Catherine J , Milne, Katy , Berrington de Gonzalez, Amy , Blome, Freya , Bodelon, Clara , Christie, Elizabeth L , Ekici, Arif B , Ghatage, Prafull , Hettiaratchi, Anusha , Jones, Michael E , Kommoss, Felix , Lambrechts, Diether , Lee, Cheng-Han , Leung, Yee , Linder, Anna , McNeish, Iain A , Nelson, Gregg S , Nevins, Nikilyn , Ray-Coquard, Isabelle L. , Roxburgh, Patricia , Van de Vijver, Koen , Wahner-Hendrickson, Andrea, Wang, Chen , Wentzensen, Nicolas , Winham, Stacey J , Anglesio, Michael S , Cohen, Paul , Conrads, Thomas , Fasching, Peter A , Horlings, Hugo , Karlan, Beth Y , Menon, Usha , Neuhausen, Susan L. , Brenton, James D , Pharoah, Paul D P , Goode, Ellen L , Ramus, Susan J , Köbel, Martin , Nelson, Brad H , Fazio, Anna de , Friedlander, Michael , Lambrechts, Diether , Brand, Alison H , Bowtell, David D , Goodman, Marc T , Zwimpfer, Tibor A. , Fereday, Sián , Jayawardana, Madawa , Twomey, Laura , Kennedy, Catherine J. , Bolithon, Adelyn , Meagher, Nicola S. , Milne, Katy , Cazorla, Alicia , Chiu, Derek S , Christie, Elizabeth L. , Chudecka-Glaz, Anita Monika , Ekici, Arif B. , Elishaev, Esther , Engler, Tobias , Fischer, Anna, García‐Closas, Montserrat , Gentry‐Maharaj, Aleksandra , Glasspool, Rosalind , Hartkopf, Andreas D , Hernandez, Brenda Y. , Kaznowska, Ewa B. , Kluz, Tomasz , Kruitwagen, Roy F.P.M. , Kwon, Jessica, Lee, Cheng‐Han , Lester, Jenny, Leung, Samuel, Linder, Anna , Lissowska, Jolanta , Lubiński, Jan , Moubarak, Malak , Nelson, Gregg , Olbrecht, Siel , Rodríguez‐Antona, Cristina , Schoemaker, Minouk J. , Sinn, Hans‐Peter , Sonke, Gabe S. , Steele, Linda, Taylor, Sarah E , Nieuwenhuysen, Els Van , Wang, Chen , Wilkens, Lynne R. , Winham, Stacey J. , Anglesio, Michael S. , Reis, Francisco José Cândido dos , Cohen, Paul A. , Crowe, Philip John , Doherty, Jennifer A. , Fortner, Renée T. , García, María J. , Goodman, Marc T. , Gronwald, Jacek , Harris, Holly R. , Heitz, Florian , Karlan, Beth Y. , Sundfeldt, Karin , Brenton, James D. , Pharoah, Paul D.P. , Ramus, Susan J. , Köbel, Martin , Nelson, Brad H. , DeFazio, Anna , Friedländer, Michael
No container title available | October 3, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
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 (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-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.
CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
Kang, Eunyoung , Weir, Ashley , Meagher, Nicola S. , Farrington, Kyo , Nelson, Gregg , Lee, Cheng‐Han , Riggan, Marjorie J. , Popović, Gordana , Leung, Betty, Tang, Katrina , Lambie, Neil, Millstein, Joshua , Alsop, Jennifer , Anglesio, Michael S. , Barlow, Ellen , Beckmann, Matthias W. , Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans , Boros, Jessica , Brand, Alison H. , Carney, Michael E. , Casablanca, Yovanni , Cohen, Paul A. , Coulson, Penny , Courtney‐Brooks, Madeleine , Cunningham, Julie M. , Darcy, Kathleen M. , El‐Bahrawy, Mona A., Farrell, Rhonda , Fischer, Anna , García, María J. , Gayther, Simon A. , Group, AOCS, Harnett, Paul R. , Harrington, Shariska P. , Harter, Philipp , Hartmann, Arndt , Hecht, Jonathan L. , Heikaus, Sebastian, Hendley, Joy , Polo, Susanna Hernando, Heublein, Sabine , Hirasawa, Akira , Huntsman, David G. , Jimenez‐Liñan, Mercedes , Jones, Michael E. , Kennedy, Catherine J. , Khabele, Dineo , Lambrechts, Diether , Le, Nhu D. , Lener, Marcin , Lester, Jenny , Leung, Yee , Linder, Anna , Loverix, Liselore , Madan, Rashna , Maxwell, G. Larry , Olawaiye, Alexander , Oršulić, Sandra , Palacios, José , Pearce, Celeste Leigh , Pike, Malcolm C. , Quinn, Carmel M. , Mohan, Ganendra Raj , Rodríguez‐Antona, Cristina , Ruebner, Matthias , Ryan, Andy , Salfinger, Stuart , Sasamoto, Naoko , Schildkraut, Joellen M. , Schoemaker, Minouk J. , Shah, Mitul , Sharma, Raghwa , Shvetsov, Yurii B. , Singh, Naveena , Steele, Linda , Stewart, Colin J.R. , Talhouk, Aline , Tan, Adeline , Terry, Kathryn L. , Tołoczko, Aleksandra, Aa, Maaike A. van der , Gorp, Toon Van , Nieuwenhuysen, Els Van , van‐Wagensveld, Lilian, Vergote, Ignace , Wu, Anna H. , Reis, Francisco José Cândido dos , Fasching, Peter A. , Goode, Ellen L. , Goodman, Marc T. , Kommoss, Stefan , Menon, Usha , Sinn, Hans‐Peter , Staebler, Annette , Bowtell, David D.L. , Ramus, Susan J. , Lambrechts, Diether , El‐Bahrawy, Mona , Lee, Cheng-Han , Fereday, Sian , Kennedy, Catherine J , Sasamoto, Naoko , Schildkraut, Joellen M , Talhouk, Aline , Vergote, Ignace , Köbel, Martin , Lambrechts, Diether , Ramus, Susan J , Rodríguez-Antona, Cristina , Menon, Usha , Sinn, Peter , Anglesio, Michael S , Jones, Michael E , Lambrechts, Diether , Brand, Alison H , Bowtell, David D , Nelson, Gregg S , El-Bahrawy, Mona A , Harnett, Paul R , Schoemaker, Minouk J , Goodman, Marc T , Linder, Anna , Cohen, Paul , Kang, Eun‐Young, Ghatage, Prafull , Bolithon, Adelyn , Ataseven, Beyhan , Brooks‐Wilson, Angela , Brucker, Sara Yvonne , Cazorla, Alicia , Conrads, Thomas , Cook, Linda S. , Cramer, Daniel W. , Crowe, Philip John , Cybulski, Cezary , Elishaev, Esther , Erber, Ramona , Fereday, Sián , Gentry‐Maharaj, Aleksandra , Gilks, C. Blake , Group, AOCS, Grube, Marcel , Hein, Alexander , Heitz, Florian , Hernandez, Brenda Y. , Høgdall, Estrid , Høgdall, Claus , Horlings, Hugo , Huzarski, Tomasz , Jewell, Andrea , Kaufmann, Scott H. , Kommoss, Felix , Kruitwagen, Roy F.P.M. , Lubiński, Jan , Modugno, Francesmary , Neuhausen, Susan L. , Olbrecht, Siel , Sonke, Gabe S. , Sundfeldt, Karin , Swerdlow, Anthony J. , Taylor, Sarah E. , Traficante, Nadia , Van de Vijver, Koen , Vierkant, Robert A. , Wang, Chen , Wilkens, Lynne R. , Winham, Stacey J. , Benı́tez, Javier , Berchuck, Andrew , DeFazio, Anna , Gronwald, Jacek , Karlan, Beth Y. , Brenton, James D. , Pharoah, Paul D.P. , Köbel, Martin
Cancer | December 27, 2022 | Volume: 129 | Issue: 5 | Pages: 697-713
AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.