Separating the BRCA1 and BRCA2 phenotype: a genomic pathway analysis

Abstract

<h3>Objectives:</h3> Emerging data suggests that key differences exist between <i>BRCA1</i> and <i>BRCA2</i> associated ovarian cancer, including response to therapy and survival outcomes. The purpose of this study was to identify gene expression profiles and interacting pathways unique to <i>BRCA1-</i> and <i>BRCA2-</i> associated high grade serous ovarian cancer (HGSOC) samples compared to one another as well as to <i>BRCA</i> wild type, homologous recombination proficient (HRP) tumors. <h3>Methods:</h3> Of 657 total HGSOC samples, 15 <i>BRCA2</i> mutated (2.2%), 16 (2.4%) <i>BRCA1</i> mutated, and 375 (57%) HRP samples were analyzed. <i>BRCA</i> mutated was defined as somatic variants that result in loss of function. The HRP control group was defined as samples negative for aberrations in <i>BRCA1/2</i> and 28 HR genes. Gene expression data was collected from Tempus and unpaired t-tests were used to identify differentially expressed genes (DEG) with p-value <0.05 and fold change (FC) of 1.5. Meta and pathway analyses were performed among <i>BRCA1</i>, <i>BRCA2</i> and HRP groups using Venn diagram and Advaita Bio's iPathwayGuide. <h3>Results:</h3> From 18,284 genes with measured expression, 843 (4.6%) DEG were found between <i>BRCA2</i> vs <i>BRCA1,</i> 748 (4.1%) between <i>BRCA2</i> vs HRP and 1,858 (10.2%) between <i>BRCA1</i> and HRP. 8,296 mutated genes were similarly expressed in both <i>BRCA2</i> and <i>BRCA1</i> groups with FC < 1.5, including DNA damage response genes <i>ATM</i> (log2FC = -0.43, p=0.51), <i>CHEK2</i> (log2FC= -0.21, p=0.79), <i>TP53</i> (log2FC = -0.73, p=0.52) and <i>PARP1</i> (log2FC=0.62, p=0.26). For <i>BRCA1</i> compared to HRP group, 214 miRNAs and 137 gene upstream regulators were identified unique to <i>BRCA1</i>; top identified pathways were metabolism related. For <i>BRCA2</i> compared to HRP group, no miRNAs and 108 gene upstream regulators were identified; identified pathways were Wnt signaling related. On meta-analysis of the 3 comparisons, 550 DEGs were found for <i>BRCA2</i> and 82 DEG for <i>BRCA1</i> that were not shared by HRP group (Figure 1). Pathway analysis revealed significant involvement of Wnt signaling pathway unique to <i>BRCA2</i> group compared to fibroblast growth factor signaling and PI3K-Akt signaling for <i>BRCA1</i>. <h3>Conclusions:</h3> Our study identified genomic signatures for <i>BRCA2</i> versus <i>BRCA1</i> associated ovarian cancer, not shared by control HRP tumors in a sample representative of HGSOC tumor heterogeneity. Results suggest <i>BRCA1/2</i> should not be considered a single entity, but rather separate phenotypes each with unique opportunities for targeted therapy.