TY - JOUR
T1 - 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
AU - Heinze, Karolin
AU - Nazeran, Tayyebeh M.
AU - Lee, Sandra
AU - Krämer, Pauline
AU - Cairns, Evan S.
AU - Chiu, Derek S.
AU - Leung, Samuel C.Y.
AU - Kang, Eun Young
AU - Meagher, Nicola S.
AU - Kennedy, Catherine J.
AU - Boros, Jessica
AU - Kommoss, Friedrich
AU - Vollert, Hans Walter
AU - Heitz, Florian
AU - du Bois, Andreas
AU - Harter, Philipp
AU - Grube, Marcel
AU - Kraemer, Bernhard
AU - Staebler, Annette
AU - Kommoss, Felix K.F.
AU - Heublein, Sabine
AU - Sinn, Hans Peter
AU - Singh, Naveena
AU - Laslavic, Angela
AU - Elishaev, Esther
AU - Olawaiye, Alex
AU - Moysich, Kirsten
AU - Modugno, Francesmary
AU - Sharma, Raghwa
AU - Brand, Alison H.
AU - Harnett, Paul R.
AU - DeFazio, Anna
AU - Fortner, Renée T.
AU - Lubinski, Jan
AU - Lener, Marcin
AU - Tołoczko-Grabarek, Aleksandra
AU - Cybulski, Cezary
AU - Gronwald, Helena
AU - Gronwald, Jacek
AU - Coulson, Penny
AU - El-Bahrawy, Mona A.
AU - Jones, Michael E.
AU - Schoemaker, Minouk J.
AU - Swerdlow, Anthony J.
AU - Gorringe, Kylie L.
AU - Campbell, Ian
AU - Cook, Linda
AU - Gayther, Simon A.
AU - Carney, Michael E.
AU - Shvetsov, Yurii B.
AU - Hernandez, Brenda Y.
AU - Wilkens, Lynne R.
AU - Goodman, Marc T.
AU - Mateoiu, Constantina
AU - Linder, Anna
AU - Sundfeldt, Karin
AU - Kelemen, Linda E.
AU - Gentry-Maharaj, Aleksandra
AU - Widschwendter, Martin
AU - Menon, Usha
AU - Bolton, Kelly L.
AU - Alsop, Jennifer
AU - Shah, Mitul
AU - Jimenez-Linan, Mercedes
AU - Pharoah, Paul D.P.
AU - Brenton, James D.
AU - Cushing-Haugen, Kara L.
AU - Harris, Holly R.
AU - Doherty, Jennifer A.
AU - Gilks, Blake
AU - Ghatage, Prafull
AU - Huntsman, David G.
AU - Nelson, Gregg S.
AU - Tinker, Anna V.
AU - Lee, Cheng Han
AU - Goode, Ellen L.
AU - Nelson, Brad H.
AU - Ramus, Susan J.
AU - Kommoss, Stefan
AU - Talhouk, Aline
AU - Köbel, Martin
AU - Anglesio, Michael S.
N1 - Publisher Copyright:
© 2021 The Pathological Society of Great Britain and Ireland.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - ARID1A
KW - CD8
KW - DNA mismatch repair
KW - clear cell ovarian carcinoma
KW - endometrioid ovarian carcinoma
KW - endometriosis-associated ovarian carcinoma
KW - immunohistochemistry
KW - prognosis
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UR - http://www.scopus.com/inward/citedby.url?scp=85122869154&partnerID=8YFLogxK
U2 - 10.1002/path.5849
DO - 10.1002/path.5849
M3 - Article
C2 - 34897700
AN - SCOPUS:85122869154
SN - 0022-3417
VL - 256
SP - 388
EP - 401
JO - Journal of Pathology
JF - Journal of Pathology
IS - 4
ER -