Objective High glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type BRCA1 promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status.
Methods Whole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR/nuclear receptor subfamily 3 C1 (NR3C1) gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis.
Results Combined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in BRCA1 or BRCA2. In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 mRNA level was observed.
Conclusions Increased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome.
- Epithelial ovarian cancer
- hormone receptor
- glucocorticoid receptor
- BRCA mutations
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Funding The authors have received support from the University of Chicago Cancer Research Foundation Women’s Board (SDC, GFF), and T32CA009566-29 (JTV). The Center for Research Informatics is funded by the Biological Sciences Division at the University of Chicago with additional funding provided by the Institute for Translational Medicine, CTSA grant number UL1 TR000430 from the National Institutes of Health. The University of Chicago Cancer Center is supported by P30CA014599-42.
Competing interests SDC and The University of Chicago have been issued patents on methods of measuring GR expression in triple-negative breast cancer (TNBC) and using GR antagonists in TNBC, which while not directly related to this work on ovarian cancer, could be considered broadly relevant. The spouse of JTV has been employed at Abbott Laboratories and Takeda. JEC reports contributions from UpToDate, Inc, outside the submitted work.
Provenance and peer review Not commissioned, externally peer reviewed.