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.
Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)
Talhouk, Aline , Wang, Chen , Budden, Timothy , Kommoss, Stefan , Leong, Huei San, Intermaggio, Maria P., Nazeran, Tayyebeh M., Volchek, Mila, Elatre, Wafaa, Chow, Veronica, Sudderuddin, Hanwei , Mackenzie, Robertson, Leong, Samuel C.Y., Liu, Geyi, Johnson, Dustin, Chen, Billy, Group, AOCS, Alsop, Jennifer , Banerjee, Susana , Bodelón, Clara , Brand, Alison H. , Brinton, Louise A. , Carney, Michael E. , Chiew, Yoke-Eng , Cushing‐Haugen, Kara L. , Ennis, Darren , Fereday, Sián , Fortner, Renée T. , Greene, Casey S. , Hendley, Joy , Hernandez, Brenda Y. , Herpel, Esther , Jimenez‐Liñan, Mercedes , Karpinskyj, Chloe , Keeney, Gary L., Kennedy, Catherine J. , Köbel, Martin , Koziak, Jennifer M. , Lester, Jenny , Lewsley, Liz-Anne , Lissowska, Jolanta , Luk, Hugh, Mahner, Sven� , McNeish, Iain A. , Menkiszak, Janusz , Nevins, Nikilyn, Osório, Ana , Oszurek, Oleg, Pearce, Celeste Leigh , Pike, Malcolm C. , Piskorz, Anna , Rhenius, Valerie , Rodríguez‐Antona, Cristina , Sharma, Raghwa , Silva, Dilrini De , Singh, Naveena , Sinn, Hans‐Peter , Slamon, Dennis J. , Song, Honglin , Steed, Helen , Stronach, Euan A. , Thompson, Pamela J., Tołoczko, Aleksandra, Trabert, Britton , Traficante, Nadia , Tseng, Chiu-Chen , Widschwendter, Martin , Winterhoff, Boris , Beeghly‐Fadiel, Alicia, Brown, Robert , Chang‐Claude, Jenny , Chenevix‐Trench, Georgia , DeFazio, Anna , Fasching, Peter A. , García, María J. , Gayther, Simon A. , Goodman, Marc T. , Henderson, Michelle J. , Kelemen, Linda E. , Menon, Usha , Oršulić, Sandra , Wentzensen, Nicolas , Wu, Anna H. , Schildkraut, Joellen M. , Rossing, Mary Anne, Konecny, Gottfried E. , Huntsman, David G. , Huang, Ruby Yun‐Ju , Goode, Ellen L. , Ramus, Susan J. , Bowtell, David D.L. , Anglesio, Michael S. , George, Joshy , Wang, Chen , Tan, Tuan Zea , Behrens, Sabine , Bodelon, Clara , Brinton, Louise A , Fortner, Renée T , García-Donas, Jesús , Gentry‐Maharaj, Aleksandra , Glasspool, Rosalind , Greene, Casey S , Haluska, Paul , Harris, Holly R , Kaufmann, Scott H , Kennedy, Catherine J , Köbel, Martin , Koziak, Jennifer M , Lissowska, Jolanta , McNeish, Iain A , Menkiszak, Janusz , Hinsley, Samantha , Pike, Malcolm C , Rodríguez-Antona, Cristina , Sinn, Peter , Trabert, B , Widschwendter, Martin , Winham, Stacey J , Brenton, James D , Brown, Robert , Chang-Claude, Jenny , Fazio, Anna de , Fasching, Peter A , Kelemen, Linda E , Menon, Usha , Pharoah, Paul D P , Ramus, Susan J , Doherty, Jennifer A , Anglesio, Michael S , Chenevix-Trench, Georgia , Brand, Alison H , Ennis, Darren P , Traficante, Nadia , Bowtell, David D , Fereday, Sian , Hernandez, Brenda Y , Steed, Helen , Goodman, Marc T , Nevins, Nikilyn , George, Joshy , Chiu, Derek S , Chen, Stephanie , Gilks, C. Blake , Bentley, Rex C. , Senz, Janine , Lum, Amy M. , Group, AOCS, Behrens, Sabine , Cybulski, Cezary , García-Donás, Jesús , Glasspool, Rosalind , Goranova, Teodora , Harris, Holly R. , Kaufmann, Scott H. , Larson, Melissa C. , Lubiński, Jan , Macintyre, Geoff , Palacios, José , Ray-Coquard, Isabelle L. , Sherman, Mark E. , Wilkens, Lynne R. , Winham, Stacey J. , Beeghly‐Fadiel, Alicia , Benı́tez, Javier , Berchuck, Andrew , Brenton, James D. , Gronwald, Jacek , Karlan, Beth Y. , Pharoah, Paul D.P. , Doherty, Jennifer A.
Clinical Cancer Research | June 17, 2020 | Volume: 26 | Issue: 20 | Pages: 5411-5423
Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271