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.
Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8
Heinze, Karolin , Nazeran, Tayyebeh M., Lee, Sandra , Krämer, Pauline , Leung, Samuel , Kang, Eun Young , Meagher, Nicola S. , Kennedy, Catherine J. , Boros, Jessica , Kommoss, Friedrich, Vollert, Hans‐Walter, Harter, Philipp , Kraemer, Bernhard , Staebler, Annette , Heublein, Sabine , Sinn, Hans‐Peter , Singh, Naveena , Laslavic, Angela , Olawaiye, Alex, Moysich, Kirsten B. , Sharma, Raghwa , Brand, Alison H. , Harnett, Paul R. , DeFazio, Anna , Fortner, Renée T. , Lener, Marcin , Tołoczko‐Grabarek, Aleksandra, Coulson, Penny , El‐Bahrawy, Mona , Jones, Michael E. , Schoemaker, Minouk J. , Gayther, Simon A. , Carney, Michael E. , Shvetsov, Yurii B. , Hernandez, Brenda Y. , Goodman, Marc T. , Mateoiu, Constantina , Linder, Anna , Kelemen, Linda E. , Widschwendter, Martin , Menon, Usha , Alsop, Jennifer , Shah, Mitul , Jimenez‐Liñan, Mercedes , Brenton, James D. , Cushing‐Haugen, Kara L. , Huntsman, David G. , Nelson, Gregg , Tinker, Anna V. , Goode, Ellen L. , Ramus, Susan J. , Kommoss, Stefan , Talhouk, Aline , Köbel, Martin , Anglesio, Michael S. , Campbell, Ian G , Gilks, C. Blake , Köbel, Martin , Anglesio, Michael S , Fazio, Anna de , Fortner, Renée T , Ramus, Susan J , Menon, Usha , Brenton, James D , Moysich, Kirsten , Kennedy, Catherine J , Sinn, Peter , Widschwendter, Martin , Jones, Michael E , Brand, Alison H , Nelson, Gregg S , El-Bahrawy, Mona A , Harnett, Paul R , Hernandez, Brenda Y , Schoemaker, Minouk J , Goodman, Marc T , Linder, Anna , Cairns, Evan S. , Chiu, Derek S , Heitz, Florian , Bois, Andreas du , Grube, Marcel , Kommoss, Felix , Elishaev, Esther , Modugno, Francesmary , Lubiński, Jan , Cybulski, Cezary , Gronwald, Helena , Gronwald, Jacek , Swerdlow, Anthony J. , Gorringe, Kylie L. , Campbell, Ian , Cook, Linda S. , Wilkens, Lynne R. , Sundfeldt, Karin , Gentry‐Maharaj, Aleksandra , Bolton, Kelly L. , Pharoah, Paul D.P. , Harris, Holly R. , Doherty, Jennifer A. , Ghatage, Prafull , Lee, Cheng‐Han , Nelson, Brad H.
The Journal of Pathology | December 13, 2021 | Volume: 256 | Issue: 4 | Pages: 388-401
Abstract ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis‐associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all samples. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8 + tumour‐infiltrating lymphocytes (CD8 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8 + TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients ( p = 0.012) and was associated with MMRd ( p < 0.001) and the presence of CD8 + TILs ( p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss‐of‐function mutation as a result of small indels ( p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8 + TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8 + TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss‐of‐function mutations in endometriosis‐associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.