Dataset Information

Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer.

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.

SUBMITTER: Wu J

PROVIDER: S-EPMC6896043 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer.

Wu Jiande J Mamidi Tarun Karthik Kumar TKK Zhang Lu L Hicks Chindo C

Cancers 20191031 11

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, so ...[more]

PMID: 31683572

Similar Datasets

Project description:BackgroundBreast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer.MethodsWe addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations.ResultsThe investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC.ConclusionsThe results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.

Project description:BackgroundMajority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa.MethodsWe addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype.ResultsThe investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa.ConclusionsThe study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.

Dataset Information

Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer.

Publications

Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets