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 C.Y. Leung, Eun Young Kang, Nicola S. Meagher, Catherine J. Kennedy, Jessica Boros, Friedrich Kommoss, Hans Walter Vollert, Florian Heitz, Andreas du Bois, Philipp Harter, Marcel Grube, Bernhard Kraemer, Annette Staebler, Felix K.F. KommossSabine Heublein, Hans Peter Sinn, Naveena Singh, Angela Laslavic, Esther Elishaev, Alex Olawaiye, Kirsten Moysich, Francesmary Modugno, Raghwa Sharma, Alison H. Brand, Paul R. Harnett, Anna DeFazio, Renée T. Fortner, Jan Lubinski, Marcin Lener, Aleksandra Tołoczko-Grabarek, Cezary Cybulski, Helena Gronwald, Jacek Gronwald, Penny Coulson, Mona A. El-Bahrawy, Michael E. Jones, Minouk J. Schoemaker, Anthony J. Swerdlow, Kylie L. Gorringe, Ian Campbell, 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, Martin Widschwendter, Usha Menon, Kelly L. Bolton, Jennifer Alsop, Mitul Shah, Mercedes Jimenez-Linan, Paul D.P. Pharoah, James D. Brenton, Kara L. Cushing-Haugen, Holly R. Harris, Jennifer A. Doherty, Blake Gilks, Prafull Ghatage, David G. Huntsman, Gregg S. Nelson, Anna V. Tinker, Cheng Han Lee, Ellen L. Goode, Brad H. Nelson, Susan J. Ramus, Stefan Kommoss, Aline Talhouk, Martin Köbel, Michael S. Anglesio

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


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.

Original languageEnglish
Pages (from-to)388-401
Number of pages14
JournalJournal of Pathology
Issue number4
StatePublished - Apr 2022


  • ARID1A
  • CD8
  • DNA mismatch repair
  • clear cell ovarian carcinoma
  • endometrioid ovarian carcinoma
  • endometriosis-associated ovarian carcinoma
  • immunohistochemistry
  • prognosis


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