AUTHOR=Li Yue , Dong Wei , Zhang Pengqian , Zhang Ting , Ma Ling , Qu Meng , Ma Xingcong , Zhou Xiaoyan , He Qian 

TITLE=Comprehensive Analysis of Regulatory Factors and Immune-Associated Patterns to Decipher Common and BRCA1/2 Mutation-Type-Specific Critical Regulation in Breast Cancer

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.750897

DOI=10.3389/fcell.2021.750897

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold><italic>BRCA</italic>1/2 mutations are closely related to high lifetime risk of breast cancer (BC). The objective of this study was to identify the genes, regulators, and immune-associated patterns underlying disease pathology in BC with <italic>BRCA1/2</italic> somatic mutations and their associations with clinical traits.</p><p><bold>Methods:</bold> RNA sequencing data and clinical information from The Cancer Genome Atlas (TCGA; <italic>N</italic> = 36 <italic>BRCA1</italic>-mutant BC; <italic>N</italic> = 49 <italic>BRCA2</italic>-mutant BC; and <italic>N</italic> = 117 <italic>BRCA1/2</italic>-wild-type BC samples) were used for discovery, which included consensus network analysis, function enrichment, and analysis of hub genes; other TCGA data (<italic>N</italic> = 117 triple-negative BC) and two Gene Expression Omnibus database expression profiles were used as validation cohorts.</p><p><bold>Results:</bold> Consensus network analysis helped to identify specific co-expressed modules that showed positive correlations with tumor stage, number of positive lymph nodes, and margin status in <italic>BRCA1/2</italic>-mutant BC but lacking correlations in <italic>BRCA1/2</italic>-wild-type BC. Functional enrichment suggested potential mechanisms in <italic>BRCA1/2</italic> carriers that could regulate the cell cycle, immune response, cellular metabolic processes, and cell migration, via enriched pathways including p53 and JAK–STAT signaling. Consensus network analysis identified the specific and common carcinogenic mechanisms involving <italic>BRCA</italic> mutations. Regulators cross-linking these modules include E2F or IRF transcription factor family, associated with cell cycle or immune response regulation module, respectively. Eight hub genes, including <italic>ISG15</italic>, <italic>BUB1</italic>, and <italic>TTK</italic>, were upregulated in several <italic>BRCA1/2</italic>-mutant BC datasets and showed prognostic value in BC. Furthermore, their genetic expression was related to higher levels of immune infiltration in <italic>BRCA1/2</italic>-mutant BC, which manifested as recruitment of T helper cells (Th1 cells), follicular helper T cells, and regulatory T cells, and T cell exhaustion. Moreover, important indicators for evaluation of BC immunotherapy, tumor mutational burden and neoantigen load also positively correlated with expression of some hub genes.</p><p><bold>Conclusion:</bold> We constructed a <italic>BRCA1/2</italic> mutation-type-specific co-expressed gene network with related transcription factors and immune-associated patterns that could regulate and influence tumor metastasis and immune microenvironment, providing novel insights into the pathological process of this disease and the corresponding <italic>BRCA</italic> mutations.</p>