Interferon-γ signaling is associated with BRCA1 loss-of-function mutations in high grade serous ovarian cancer

Loss-of-function mutations of the breast cancer type 1 susceptibility protein (BRCA1) are associated with breast (BC) and ovarian cancer (OC). To identify gene signatures regulated by epigenetic mechanisms in OC cells carrying BRCA1 mutations, we assessed cellular responses to epigenome modifiers and performed genome-wide RNA- and chromatin immunoprecipitation-sequencing in isogenic OC cells UWB1.289 (carrying a BRCA1 mutation, BRCA1-null) and UWB1.289 transduced with wild-type BRCA1 (BRCA1-). Increased sensitivity to histone deacetylase inhibitors (HDACi) was observed in BRCA1-null vs. BRCA1+ cells. Gene expression profiles of BRCA1-null vs. BRCA1 cells and treated with HDACi were integrated with chromatin mapping of histone H3 lysine 9 or 27 acetylation. Gene networks activated in BRCA1-null vs. BRCA1 - OC cells related to cellular movement, cellular development, cellular growth and proliferation, and activated upstream regulators included TGF beta 1, TNF, and IFN-gamma. The IFN-gamma pathway was altered by HDACi in BRCA1+ vs. BRCA1-null cells, and in BRCA1-mutated/or low vs. BRCA1-normal OC tumors profiled in the TCGA. Key IFN-gamma-induced genes upregulated at baseline in BRCA1-null vs. BRCA1-OC and BC cells included CXCL10, CXCL11, and 1F116. Increased localization of STAT1 in the promoters of these genes occurred in BRCA1-null OC cells, resulting in diminished responses to IFN-gamma or to STAT1 knockdown. The IFN-gamma signature was associated with improved survival among OC patients profiled in the TCGA. In all, our results support that changes affecting IFN-gamma responses are associated with inactivating BRCA1 mutations in OC. This signature may contribute to altered responses to anti-tumor immunity in BRCA1-mutated cells or tumors.