1. 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.
- Author
-
Heinze K, Nazeran TM, Lee S, Krämer P, Cairns ES, Chiu DS, Leung SC, Kang EY, Meagher NS, Kennedy CJ, Boros J, Kommoss F, Vollert HW, Heitz F, du Bois A, Harter P, Grube M, Kraemer B, Staebler A, Kommoss FK, Heublein S, Sinn HP, Singh N, Laslavic A, Elishaev E, Olawaiye A, Moysich K, Modugno F, Sharma R, Brand AH, Harnett PR, DeFazio A, Fortner RT, Lubinski J, Lener M, Tołoczko-Grabarek A, Cybulski C, Gronwald H, Gronwald J, Coulson P, El-Bahrawy MA, Jones ME, Schoemaker MJ, Swerdlow AJ, Gorringe KL, Campbell I, Cook L, Gayther SA, Carney ME, Shvetsov YB, Hernandez BY, Wilkens LR, Goodman MT, Mateoiu C, Linder A, Sundfeldt K, Kelemen LE, Gentry-Maharaj A, Widschwendter M, Menon U, Bolton KL, Alsop J, Shah M, Jimenez-Linan M, Pharoah PD, Brenton JD, Cushing-Haugen KL, Harris HR, Doherty JA, Gilks B, Ghatage P, Huntsman DG, Nelson GS, Tinker AV, Lee CH, Goode EL, Nelson BH, Ramus SJ, Kommoss S, Talhouk A, Köbel M, and Anglesio MS
- Subjects
- Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Brain Neoplasms, CD8-Positive T-Lymphocytes pathology, Canada, Colorectal Neoplasms, DNA-Binding Proteins genetics, Female, Humans, Neoplastic Syndromes, Hereditary, Nuclear Proteins genetics, Prognosis, Transcription Factors genetics, Carcinoma, Endometriosis genetics, Endometriosis pathology, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- 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. © 2021 The Pathological Society of Great Britain and Ireland., (© 2021 The Pathological Society of Great Britain and Ireland.)- Published
- 2022
- Full Text
- View/download PDF