Prognostic and Immunological Significance of ARID1A Status in Endometriosis-Associated Ovarian Carcinoma
Authors: Heinze Karolin , Nazeran Tayyebeh M. , Lee Sandra , Krämer Pauline , Cairns Evan S. , Chiu Derek S. , Leung Samuel C.Y. , Kang Eun Young , Meagher Nicola S. , Kennedy Catherine J. , Boros Jessica , Kommoss Friedrich , Vollert Hans-Walter , Heitze Florian , du Bois Andreas , Harter Philipp , Grube Marcel , Kraemer Bernhard , Staebler Annette , Kommoss Felix K.F. , Heublein Sabine , Sinn Hans-Peter , Singh Naveena , Laslavic Angela , Elishaev Esther , Olawaiye Alex , Moysich Kirsten , Modugno Francesmary , Sharma Raghwa , Brand Alison H. , Harnett Paul R. , DeFazio Anna , Fortner Renée T. , Lubinski Jan , Lener Marcin , Tołoczko-Grabarek Aleksandra , Cybulski Cezary , Gronwald Helena , Gronwald Jacek , Coulson Penny , El-Bahrawy Mona A , Jones Michael E. , Schoemaker Minouk J. , Swerdlow Anthony J. , Gorringe Kylie L. , Campbell Ian , Cook Linda , Gayther Simon A. , Carney Michael E. , Shvetsov Yurii B. , Hernandez Brenda Y. , Wilkens Lynne R. , Goodman Marc T. , Mateoiu Constantina , Linder Anna , Sundfeldt Karin , Kelemen Linda E. , Gentry-Maharaj Aleksandra , Widschwendter Martin , Menon Usha , Bolton Kelly L. , Alsop Jennifer , Shah Mitul , Jimenez-Linan Mercedes , Pharoah Paul D.P. , Brenton James D. , Cushing-Haugen Kara L. , Harris Holly R. , Doherty Jennifer A. , Gilks Blake , Ghatage Prafull , Huntsman David G. , Nelson Gregg S. , Tinker Anna V. , Lee Cheng-Han , Goode Ellen L. , Nelson Brad H. , Ramus Susan J. , Kommoss Stefan , Talhouk Aline , Köbel Martin , Anglesio Michael S. 
Published: September 2021

ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumor 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+ tumor-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. 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 associated with MMRd (p<0.001), and presence of CD8+ TIL (p=0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOC we also observed an association between ARID1A loss-of-function mutation as a result of small indels (p=0.011, vs. single nucleotide variants). In ENOC, the association between ARID1A loss, CD8+ TIL, 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.