Citations 2
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.
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