Objectives To identify gene expression profiles and interacting pathways in BRCA1- and BRCA2- associated high grade serous ovarian cancer (HGSOC) as compared to one another and to BRCA wild type, homologous recombination proficient (HRP) tumors.
Methods of 657 total HGSOC samples, 15 BRCA2 mutated (2.3%), 16 (2.4%) BRCA1 mutated, and 375 (57.1%) HRP samples were analyzed. Gene expression data was collected from Tempus and unpaired t-tests were used to identify differentially expressed genes (DEG) with unadjusted p-value <0.05 and fold change of 1.5. Meta and pathway analyses were performed among BRCA1, BRCA2 and HRP groups using Venn diagram and Advaita Bio’s iPathwayGuide. BRCA mutated and wild type (wt) ID8 mouse cell lines were used for protein expression and seahorse assay for metabolism analysis.
Results From 18,284 genes with measured expression, 843 (4.6%) DEG were found between BRCA2 vs BRCA1, 748 (4.1%) between BRCA2 vs HRP and 1,858 (10.2%) between BRCA1 and HRP. On meta-analysis of the three comparisons, pathway analysis revealed significant involvement of Wnt signaling pathway and oxidative phosphorylation unique to BRCA2 group compared to fibroblast growth factor signaling and PI3K-Akt signaling for BRCA1. Western blot analysis confirmed higher expression of oxidative phosphorylation complex proteins in BRCA1/BRCA2 mutated lines and differential expression of β catenin between BRCA mutated versus wt cell lines. Seahorse assay showed higher oxidative consumption rate in BRCA mutated versus wt cells.
Conclusions Our study identified differential pathway regulation for BRCA2 versus BRCA1 associated HGSOC, suggesting each should be considered a separate phenotype with unique opportunities for targeted therapy.
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