期刊
JOURNAL OF PATHOLOGY
卷 256, 期 4, 页码 388-401出版社
WILEY
DOI: 10.1002/path.5849
关键词
clear cell ovarian carcinoma; endometrioid ovarian carcinoma; endometriosis-associated ovarian carcinoma; ARID1A; DNA mismatch repair; CD8; immunohistochemistry; prognosis
资金
- Deutsche Forschungsgesellschaft [HE 8699/1-1]
- Michael Smith Foundation for Health Research Scholar Award
- Calgary Laboratory Services research support fund [RS19-612]
- Janet D. Cottrelle Foundation Scholars program
- BC Cancer Foundation
- VGH & UBC Hospital Foundation
- Terry Fox Research Institute
- Westmead Hospital Department of Gynaecological Oncology
- National Health and Medical Research Council Enabling Grants [310670, 628903]
- Cancer Institute NSW Grants [12/RIG/1-17, 15/RIG/1-16]
- Sydney West Translational Cancer Research Centre
- Cancer Institute NSW
- Breast Cancer Now
- Institute of Cancer Research (ICR)
- NHS
- Swedish Cancer Foundation
- Assar Gabrielsson Foundation
- National Health Institute [R01-CA168758, R01-CA112523, R01-CA087538]
- German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research [01 GB 9401]
- German Cancer Research Center (DKFZ)
- National Institutes of Health
- National Cancer Institute [N01-CN-25403/CN, N01-CN-67001/CN, P30-CA-71789/CA, R01-CA-58598/CA, K07-CA80668, R01CA095023, R01 CA126841]
- US Army Medical Research and Materiel Command [DAMD17-02-1-0669]
- NIH/National Center for Research Resources/General Clinical Research Center grant [MO1RR000056]
- European Research Council Advanced Grant (H2020 BRCA-ERC) [742432]
- Cancer Research UK [C490/A10119 C490/A10124 C490/A16561]
- UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge
- Janet D. Cottrelle Foundation
- Canadian Institutes of Health Research
- Swedish government
- Swedish county council, the ALF-agreement
- European Research Council (ERC) [742432] Funding Source: European Research Council (ERC)
ARID1A (BAF250a) is an important component of the SWI/SNF chromatin modifying complex and plays a suppressor role in ovarian cancer. This study investigated the relationship between ARID1A loss/mutation and clinical features, outcomes, immune response, and DNA mismatch repair deficiency in ovarian carcinomas. The findings showed that ARID1A loss was more prevalent in clear cell ovarian carcinomas, and in endometrioid ovarian carcinomas, it was associated with younger age, DNA mismatch repair deficiency, and the presence of CD8(+) tumor-infiltrating lymphocytes. The study provides important insights into the prevalence and prognostic significance of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers.
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. (c) 2021 The Pathological Society of Great Britain and Ireland.
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