Abstract
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. Emerging evidenced suggests that both genetics and epigenetic factors play a role in the pathogenesis of TNBC. However, oncogenic interactions and cooperation between genomic and epigenomic variation have not been characterized. The objective of this study was to deconvolute the genomic and epigenomic interaction landscape in TNBC using an integrative genomics approach, which integrates information on germline, somatic, epigenomic and gene expression variation. We hypothesized that TNBC originates from a complex interplay between genomic (both germline and somatic variation) and epigenomic variation. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect entire molecular networks and signaling pathways which, in turn, drive TNBC. We addressed these hypotheses using germline variation from genome-wide association studies and somatic, epigenomic and gene expression variation from The Cancer Genome Atlas (TCGA). The investigation revealed signatures of functionally related genes containing germline, somatic and epigenetic variations. DNA methylation had an effect on gene expression. Network and pathway analysis revealed molecule networks and signaling pathways enriched for germline, somatic and epigenomic variation, among them: Role of BRCA1 in DNA Damage Response, Hereditary Breast Cancer Signaling, Molecular Mechanisms of Cancer, Estrogen-Dependent Breast Cancer, p53, MYC Mediated Apoptosis, and PTEN Signaling pathways. The investigation revealed that integrative genomics is a powerful approach for deconvoluting the genomic-epigenomic interaction landscape in TNBC. Further studies are needed to understand the biological mechanisms underlying oncogenic interactions between genomic and epigenomic factors in TNBC.
Highlights
Triple-negative breast cancer (TNBC) is a heterogeneous disease, characterized by aggressive clinical behavior, poor prognosis, a significantly increased risk of relapse, and shorter survival rates than patients affected by other molecular subtypes of breast cancer [1,2,3]
The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have generated comprehensive catalogues of somatic mutations associated with TNBC [20,21]
Levels 4 and 5 integrations were higher level integrations involving network and pathway analysis, respectively, to identify molecular networks and signaling pathways enriched for germline, somatic, epigenetic and gene expression variation
Summary
Triple-negative breast cancer (TNBC) is a heterogeneous disease, characterized by aggressive clinical behavior, poor prognosis, a significantly increased risk of relapse, and shorter survival rates than patients affected by other molecular subtypes of breast cancer [1,2,3]. TNBC is clinically defined as tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2 amplification [1,2,3]. It affects primarily younger premenopausal women and tends to have higher incidences in African American women, recent studies reported no differences in clinical outcomes between Caucasian and African American women after adjusting for socioeconomic. Cytotoxic chemotherapy remains the only effective therapeutic modality for this aggressive and often lethal type of breast cancer [3].
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