Citations 2
p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study
Köbel, Martin , Kang, Eunyoung , Weir, Ashley , Rambau, Peter , Nelson, Gregg , Meagher, Nicola S. , Riggan, Marjorie J. , Alsop, Jennifer , Anglesio, Michael S. , Beckmann, Matthias W. , Bisinotto, Christiani, Boisen, M.M. , Boros, Jessica , Brand, Alison H. , Carney, Michael E. , Coulson, Penny , Courtney‐Brooks, Madeleine , Cushing‐Haugen, Kara L. , Deen, Suha , El‐Bahrawy, Mona , Group, AOCS, Fischer, Anna , Gayther, Simon A. , Hartmann, Arndt, Hendley, Joy , Huang, Yajue, Jimenez‐Liñan, Mercedes , Jones, Michael E. , Kennedy, Catherine J. , Kluz, Tomasz , Koziak, Jennifer M. , Lesnock, Jaime, Lester, Jenny , Longacre, Teri A. , Lycke, Maria , Mateoiu, Constantina , McCauley, Bryan M. , McGuire, Valerie , Ney, Britta, Olawaiye, Alexander , Oršulić, Sandra , Osório, Ana , Paz‐Ares, Luis , Rothstein, Joseph H. , Ruebner, Matthias , Shah, Mitul , Sharma, Raghwa , Shvetsov, Yurii B. , Singh, Naveena , Talhouk, Aline , Whittemore, Alice S. , Widschwendter, Martin , Bowtell, David D.L. , Reis, Francisco José Cândido dos , Fasching, Peter A. , García, María J. , Goodman, Marc T. , Goode, Ellen L. , Huntsman, David G. , Kelemen, Linda E. , Kommoss, Stefan , Le, Nhu D. , Menon, Usha , Schildkraut, Joellen M. , Sieh, Weiva , Staebler, Annette , Ramus, Susan J. , Anglesio, Michael S , Erber, Ramona , Gilks, C. Blake , Shvetsov, Yurii B , Campbell, Ian G , Huntsman, David G , Ramus, Susan J , Köbel, Martin , Menon, Usha , Kennedy, Catherine J , Widschwendter, Martin , Jones, Michael E , Sieh, Weiva , Brand, Alison H , Bowtell, David D , Nelson, Gregg S , El-Bahrawy, Mona A , Kluz, Tomasz , Goodman, Marc T , Kang, Eun‐Young, Lee, Cheng‐Han , Ghatage, Prafull , Brooks‐Wilson, Angela , Cybulski, Cezary , Elishaev, Esther , Fereday, Sián , Group, AOCS, Barquín, Arántzazu , Gentry‐Maharaj, Aleksandra , Gronwald, Helena , Grube, Marcel , Harnett, Paul R. , Harris, Holly R. , Hartkopf, Andreas D , Hein, Alexander , Hernandez, Brenda Y. , Jakubowska, Anna , Lubiński, Jan , Cajal, Teresa Ramón y , Schoemaker, Minouk J. , Sherman, Mark E. , Steed, Helen , Storr, Sarah J. , Traficante, Nadia , Wang, Chen , Wilkens, Lynne R. , Winham, Stacey J. , Benı́tez, Javier , Berchuck, Andrew , Campbell, Ian , Cook, Linda S. , DeFazio, Anna , Doherty, Jennifer A. , Fortner, Renée T. , Gronwald, Jacek , Karlan, Beth Y. , Martin, Stewart G. , Modugno, Francesmary , Pharoah, Paul D.P. , Sundfeldt, Karin , Swerdlow, Anthony J. , Brenton, James D.
The Journal of Pathology: Clinical Research | March 22, 2023 | Volume: 9 | Issue: 3 | Pages: 208-222
AbstractOur objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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.