Abstract
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.
Highlights
Breast cancer (BC) is highly heterogeneous with potentially aggressive and complex biological features
We found that some modules associated with the clinical characteristics of BRCA2-MUT BC were related to tumor metabolism, cell migration, and other biological functions, and most candidate genes were expressed in Triple-negative BC (TNBC) (Figure 4)
Immune Response In both the BRCA1-MUT and BRCA2-MUT cohorts, we found upregulated modules significantly related to immune response, indicating that genes in these modules may have specific effects on progression and metastasis of BRCA1/2-MUT BC but no significant impact on BRCA1/2-WT BC
Summary
Breast cancer (BC) is highly heterogeneous with potentially aggressive and complex biological features. BRCA1 and BRCA2 are tumor suppressor genes with critical roles in DNA damage repair; their germline or somatic mutations are closely related to carcinogenesis, including BC and high-grade serous cancer of the gynecological tract ( the fallopian tube, ovary, and peritoneum) (Foulkes and Shuen, 2013). BRCA1/2 mutations are the most common germline mutations and confer substantial lifetime risk of tumors, accounting for up to 40% of familial BC cases (Anastasiadi et al, 2017). Owing to the introduction of PARP inhibitors and DNA damaging agents as therapies for germline BRCA1/2-mutant (BRCA1/2-MUT) advanced BC and germline/somatic BRCA-MUT ovarian cancer, the identification of non-familial BC cases with BRCA-like features is important, as these may represent a novel therapy opportunity (Tutt et al, 2018; Coleman et al, 2019; Vidula et al, 2020). 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
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