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Cell-type-specific epigenomic variations associated with BRCA1 mutation in pre-cancer human breast tissues.

ABSTRACT: BRCA1 germline mutation carriers are predisposed to breast cancers. Epigenomic regulations have been known to strongly interact with genetic variations and potentially mediate biochemical cascades involved in tumorigenesis. Due to the cell-type specificity of epigenomic features, profiling of individual cell types is critical for understanding the molecular events in various cellular compartments within complex breast tissue. Here, we produced cell-type-specific profiles of genome-wide histone modifications including H3K27ac and H3K4me3 in basal, luminal progenitor, mature luminal and stromal cells extracted from a small pilot cohort of pre-cancer BRCA1 mutation carriers (BRCA1^mut/+ ) and non-carriers (BRCA1^+/+ ), using a low-input ChIP-seq technology that we developed. We discovered that basal and stromal cells present the most extensive epigenomic differences between mutation carriers (BRCA1^mut/+ ) and non-carriers (BRCA1^+/+ ), while luminal progenitor and mature luminal cells are relatively unchanged with the mutation. Furthermore, the epigenomic changes in basal cells due to BRCA1 mutation appear to facilitate their transformation into luminal progenitor cells. Taken together, epigenomic regulation plays an important role in the case of BRCA1 mutation for shaping the molecular landscape that facilitates tumorigenesis.

SUBMITTER: Hsieh YP

PROVIDER: S-EPMC8808540 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: BRCA1/2 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 BRCA1/2 somatic mutations and their associations with clinical traits. Methods: RNA sequencing data and clinical information from The Cancer Genome Atlas (TCGA; N = 36 BRCA1-mutant BC; N = 49 BRCA2-mutant BC; and N = 117 BRCA1/2-wild-type BC samples) were used for discovery, which included consensus network analysis, function enrichment, and analysis of hub genes; other TCGA data (N = 117 triple-negative BC) and two Gene Expression Omnibus database expression profiles were used as validation cohorts. Results: 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 BRCA1/2-mutant BC but lacking correlations in BRCA1/2-wild-type BC. Functional enrichment suggested potential mechanisms in BRCA1/2 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 BRCA 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 ISG15, BUB1, and TTK, were upregulated in several BRCA1/2-mutant BC datasets and showed prognostic value in BC. Furthermore, their genetic expression was related to higher levels of immune infiltration in BRCA1/2-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. Conclusion: We constructed a BRCA1/2 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 BRCA mutations.

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Cell-type-specific epigenomic variations associated with BRCA1 mutation in pre-cancer human breast tissues.

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