| Literature DB >> 34897700 |
Karolin Heinze1,2, Tayyebeh M Nazeran2, Sandra Lee3, Pauline Krämer1,4, Evan S Cairns1, Derek S Chiu2, Samuel Cy Leung2, Eun Young Kang3, Nicola S Meagher5,6, Catherine J Kennedy7,8, Jessica Boros7,8, Friedrich Kommoss9, Hans-Walter Vollert10, Florian Heitz11, Andreas du Bois11, Philipp Harter11, Marcel Grube1,4, Bernhard Kraemer4, Annette Staebler12, Felix Kf Kommoss13, Sabine Heublein14, Hans-Peter Sinn13, Naveena Singh15, Angela Laslavic16, Esther Elishaev17, Alex Olawaiye16, Kirsten Moysich18, Francesmary Modugno16, Raghwa Sharma19,20,21, Alison H Brand8,20, Paul R Harnett8,22, Anna DeFazio7,8,20,23, Renée T Fortner24, Jan Lubinski25, Marcin Lener25, Aleksandra Tołoczko-Grabarek25, Cezary Cybulski25, Helena Gronwald26, Jacek Gronwald25, Penny Coulson27, Mona A El-Bahrawy28, Michael E Jones27, Minouk J Schoemaker27, Anthony J Swerdlow27,29, Kylie L Gorringe30,31, Ian Campbell30,32, Linda Cook33, Simon A Gayther34, Michael E Carney35, Yurii B Shvetsov36, Brenda Y Hernandez36, Lynne R Wilkens36, Marc T Goodman37, Constantina Mateoiu38, Anna Linder38, Karin Sundfeldt38, Linda E Kelemen39, Aleksandra Gentry-Maharaj40,41, Martin Widschwendter42, Usha Menon40, Kelly L Bolton43, Jennifer Alsop44, Mitul Shah45, Mercedes Jimenez-Linan45, Paul Dp Pharoah44,46, James D Brenton47, Kara L Cushing-Haugen48, Holly R Harris48, Jennifer A Doherty49, Blake Gilks2, Prafull Ghatage50, David G Huntsman1,2, Gregg S Nelson50, Anna V Tinker2,51, Cheng-Han Lee52, Ellen L Goode53, Brad H Nelson54, Susan J Ramus5,6, Stefan Kommoss4, Aline Talhouk1,2, Martin Köbel3, Michael S Anglesio1,2.
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.Entities:
Keywords: ARID1A; CD8; DNA mismatch repair; clear cell ovarian carcinoma; endometrioid ovarian carcinoma; endometriosis-associated ovarian carcinoma; immunohistochemistry; prognosis
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Year: 2022 PMID： 34897700 PMCID： PMC9544180 DOI： 10.1002/path.5849
Source DB: PubMed Journal: J Pathol ISSN： 0022-3417 Impact factor: 9.883