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
Authors: Heinze Karolin , Nazeran Tayyebeh M , Lee Sandra , Krämer Pauline , Cairns Evan S , Chiu Derek S , Leung Samuel CY , Kang Eun Young , Meagher Nicola S , Kennedy Catherine J , Boros Jessica , Kommoss Friedrich , Vollert Hans‐Walter , Heitz Florian , du Bois Andreas , Harter Philipp , Grube Marcel , Kraemer Bernhard , Staebler Annette , Kommoss Felix KF , 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 DP , 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: December 2021

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.