Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8 + TIL infiltration, and provides no independent prognostic value in endometriosis‐associated ovarian carcinomas

Karolin Heinze, Tayyebeh M Nazeran, Sandra Lee, Pauline Krämer, Evan S Cairns, Derek S Chiu, Samuel Cy Leung, Samuel Leung, Eun Young Kang, Nicola S Meagher, Catherine J Kennedy, Jessica Boros, Friedrich Kommoss, Hans‐Walter Vollert, Hans-Walter Vollert, Florian Heitz, Andreas du Bois, Philipp Harter, Marcel Grube, Bernhard Kraemer, Annette Staebler, F. Kommoss, Felix Kf Kommoss, Sabine Heublein, Hans‐Peter Sinn, Hans-Peter Sinn, Naveena Singh, Angela Laslavic, Esther Elishaev, Alex Olawaiye, Kirsten B. Moysich, Kirsten Moysich, Francesmary Modugno, Raghwa Sharma, Alison H Brand, Paul R Harnett, Anna DeFazio, Renée T Fortner, Jan Lubiński, Jan Lubinski, Marcin Lener, Aleksandra Tołoczko‐Grabarek, Aleksandra Tołoczko-Grabarek, Cezary Cybulski, Helena Gronwald, Jacek Gronwald, Penny Coulson, Mona A El-Bahrawy, Mona El‐Bahrawy, Michael E Jones, Minouk J Schoemaker, Anthony J Swerdlow, Kylie L Gorringe, Ian Campbell, Linda S. Cook, Linda Cook, Simon A Gayther, Michael E Carney, Yurii B Shvetsov, Brenda Y Hernandez, Lynne R Wilkens, Marc T Goodman, Constantina Mateoiu, Anna Linder, Karin Sundfeldt, Linda E Kelemen, Aleksandra Gentry‐Maharaj, Aleksandra Gentry-Maharaj, Martin Widschwendter, Usha Menon, Kelly L Bolton, Jennifer Alsop, Mitul Shah, Mercedes Jimenez‐Liñan, Mercedes Jimenez-Linan, Paul Dp Pharoah, Paul D.P. Pharoah, James D Brenton, Kara L Cushing-Haugen, Kara L. Cushing‐Haugen, Holly R Harris, Jennifer A Doherty, C. Blake Gilks, Prafull Ghatage, David G Huntsman, Gregg S Nelson, Gregg Nelson, Anna V Tinker, Cheng‐Han Lee, Cheng-Han Lee, Ellen L Goode, Brad H Nelson, Susan J Ramus, Stefan Kommoss, Aline Talhouk, Martin Köbel, Michael S. Anglesio
The Journal of Pathology · 2021 · vol. 256(4) , pp. 388–401 · doi:10.1002/path.5849 · PMID:34897700 · PMC9544180 · W4200136702
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In 1623 endometriosis-associated ovarian carcinomas, ARID1A loss was not prognostically significant but was associated with mismatch repair deficiency and CD8+ T-cell infiltration in endometrioid subtypes.

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Abstract

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.

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Condition tags

endometriosis

MeSH descriptors

Carcinoma Endometriosis Endometriosis Endometriosis Ovarian Neoplasms Ovarian Neoplasms Ovarian Neoplasms Biomarkers, Tumor Biomarkers, Tumor Biomarkers, Tumor Brain Neoplasms Canada CD8-Positive T-Lymphocytes CD8-Positive T-Lymphocytes Colorectal Neoplasms DNA-Binding Proteins DNA-Binding Proteins Female Humans Neoplastic Syndromes, Hereditary

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