scholarly journals Unraveling the Genomic-Epigenomic Interaction Landscape in Triple Negative and Non-Triple Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1559
Author(s):  
Jiande Wu ◽  
Tarun Karthik Kumar Mamidi ◽  
Lu Zhang ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Signaling Pathways ◽  
Somatic Mutation ◽  
Gene Expression Data ◽  
Triple Negative Breast Cancer ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Expression Data ◽  
Gene Expression Signatures

Background: The recent surge of next generation sequencing of breast cancer genomes has enabled development of comprehensive catalogues of somatic mutations and expanded the molecular classification of subtypes of breast cancer. However, somatic mutations and gene expression data have not been leveraged and integrated with epigenomic data to unravel the genomic-epigenomic interaction landscape of triple negative breast cancer (TNBC) and non-triple negative breast cancer (non-TNBC). Methods: We performed integrative data analysis combining somatic mutation, epigenomic and gene expression data from The Cancer Genome Atlas (TCGA) to unravel the possible oncogenic interactions between genomic and epigenomic variation in TNBC and non-TNBC. We hypothesized that within breast cancers, there are differences in somatic mutation, DNA methylation and gene expression signatures between TNBC and non-TNBC. We further hypothesized that genomic and epigenomic alterations affect gene regulatory networks and signaling pathways driving the two types of breast cancer. Results: The investigation revealed somatic mutated, epigenomic and gene expression signatures unique to TNBC and non-TNBC and signatures distinguishing the two types of breast cancer. In addition, the investigation revealed molecular networks and signaling pathways enriched for somatic mutations and epigenomic changes unique to each type of breast cancer. The most significant pathways for TNBC were: retinal biosynthesis, BAG2, LXR/RXR, EIF2 and P2Y purigenic receptor signaling pathways. The most significant pathways for non-TNBC were: UVB-induced MAPK, PCP, Apelin endothelial, Endoplasmatic reticulum stress and mechanisms of viral exit from host signaling Pathways. Conclusion: The investigation revealed integrated genomic, epigenomic and gene expression signatures and signing pathways unique to TNBC and non-TNBC, and a gene signature distinguishing the two types of breast cancer. The study demonstrates that integrative analysis of multi-omics data is a powerful approach for unravelling the genomic-epigenomic interaction landscape in TNBC and non-TNBC.

scholarly journals Evaluation of Gene Expression Data From Cybrids and Tumours Highlights Elevated NDRG1-Driven Proliferation in Triple-Negative Breast Cancer

2020 ◽  
Vol 14 ◽  
pp. 117822342093444
Author(s):  
Akanksha Mishra ◽  
Maria Bonello ◽  
Adam Byron ◽  
Simon P Langdon ◽  
Andrew H Sims
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Gene Expression Data ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Donor Cell ◽  
Expression Data ◽  
Donor Cells

Background: Triple-negative breast cancer is an aggressive type of breast cancer with high risk of recurrence. It is still poorly understood and lacks any targeted therapy, which makes it difficult to treat. Thus, it is important to understand the underlying mechanisms and pathways that are dysregulated in triple-negative breast cancer. Methods: To investigate the role of mitochondria in triple-negative breast cancer progression, we analysed previously reported gene expression data from triple-negative breast cancer cybrids with SUM-159 as the nuclear donor cell and SUM-159 or A1N4 (c-SUM-159, c-A1N4) as the mitochondrial donor cells and with 143B as the nuclear donor cell and MCF-10A or MDA-MB-231 (c-MCF-10A, c-MDA-MB-231) as the mitochondrial donor cells. The role of potential biomarkers in cell proliferation and migration was examined in SUM-159 and MDA-MB-231 cells using sulforhodamine B and wound healing assays. Results: Rank product analysis of cybrid gene expression data identified 149 genes which were significantly up-regulated in the cybrids with mitochondria from the cancer cell line. Analysis of previously reported breast tumour gene expression datasets confirmed 9 of the 149 genes were amplified, up-regulated, or down-regulated in more than 10% of the patients. The genes included NDRG1, PVT1, and EXT1, which are co-located in cytoband 8q24, which is frequently amplified in breast cancer. NDRG1 showed the largest down-regulation in the cybrids with benign mitochondria and was associated with poor prognosis in a breast cancer clinical dataset. Knockdown of NDRG1 expression significantly decreased proliferation of SUM-159 triple-negative breast cancer cells. Conclusions: These results indicate that mitochondria-regulated nuclear gene expression helps breast cancer cells survive and proliferate, consistent with previous work focusing on an Src gene signature which is mitochondria regulated and drives malignancy in breast cancer cybrids. This is the first study to show that mitochondria in triple-negative breast cancer mediate significant up-regulation of a number of genes, and silencing of NDRG1 leads to significant reduction in proliferation.

scholarly journals An Integrative Genomics Approach for Associating GWAS Information with Triple-Negative Breast Cancer

2013 ◽  
Vol 12 ◽  
pp. CIN.S10413 ◽  
Author(s):  
Chindo Hicks ◽  
Ranjit Kumar ◽  
Antonio Pannuti ◽  
Kandis Backus ◽  
Alexandra Brown ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Gene Expression Data ◽  
Triple Negative Breast Cancer ◽  
Genetic Variants ◽  
Triple Negative ◽  
Genome Wide Association Studies ◽  
Expression Data ◽  
Integrative Genomics ◽  
Increased Risk

Genome-wide association studies (GWAS) have identified genetic variants associated with an increased risk of developing breast cancer. However, the association of genetic variants and their associated genes with the most aggressive subset of breast cancer, the triple-negative breast cancer (TNBC), remains a central puzzle in molecular epidemiology. The objective of this study was to determine whether genes containing single nucleotide polymorphisms (SNPs) associated with an increased risk of developing breast cancer are connected to and could stratify different subtypes of TNBC. Additionally, we sought to identify molecular pathways and networks involved in TNBC. We performed integrative genomics analysis, combining information from GWAS studies involving over 400,000 cases and over 400,000 controls, with gene expression data derived from 124 breast cancer patients classified as TNBC (at the time of diagnosis) and 142 cancer-free controls. Analysis of GWAS reports produced 500 SNPs mapped to 188 genes. We identified a signature of 159 functionally related SNP-containing genes which were significantly ( P < 10−5) associated with and stratified TNBC. Additionally, we identified 97 genes which were functionally related to, and had similar patterns of expression profiles, SNP-containing genes. Network modeling and pathway prediction revealed multi-gene pathways including p53, NFkB, BRCA, apoptosis, DNA repair, DNA mismatch, and excision repair pathways enriched for SNPs mapped to genes significantly associated with TNBC. The results provide convincing evidence that integrating GWAS information with gene expression data provides a unified and powerful approach for biomarker discovery in TNBC.

scholarly journals Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer

2019 ◽  
Vol 16 (6) ◽  
pp. 1055 ◽  
Author(s):  
Jiande Wu ◽  
Tarun Mamidi ◽  
Lu Zhang ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Somatic Mutation ◽  
Triple Negative Breast Cancer ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Germline Mutations ◽  
Biological Pathways ◽  
Molecular Networks ◽  
Increased Risk ◽  
Mutation Information

Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of BRCA1 in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.

Characterization of the tumor immune microenvironment of triple-negative breast cancer (TNBC) patients who self-identify as African American (AA) or non-African American (NonAA).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 564-564
Author(s):  
Kim Blenman ◽  
Michal Marczyk ◽  
Tao Qing ◽  
Tess O'Meara ◽  
Vesal Yaghoobi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
African American ◽  
Triple Negative Breast Cancer ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Immune Microenvironment ◽  
Gene Level ◽  
Tumor Immune Microenvironment ◽  
Pathway Level

564 Background: What tumor biological differences, if any, contribute to the higher incidence and worse prognosis of triple negative breast cancer (TNBC) in African American (AA) compared to NonAA patients are unknown. We hypothesized that differences in the tumor immune microenvironment may contribute to the outcome disparities. The purpose of this study was to characterize and compare the immune microenvironment of TNBC between patients self-identified as NonAA or AA. Methods: Formalin fixed paraffin embedded surgically resected cancer and paired normal tissues collected before any systemic therapy and the corresponding clinical data were collected for NonAA (n = 56) and AA (n = 54) stage I-III TNBC treated at Yale Cancer Center between 2000-2017. The two cohorts were matched for clinical stage, age of diagnosis, and year of diagnosis. We performed somatic and germline whole exome sequencing (WES), bulk RNA sequencing, and immunohistochemistry to assess PD-L1 expression (SP142). Stromal tumor infiltrating lymphocytes (sTILs) were assessed on H&E slides. Mutation load, mutation frequencies, and gene expression differences were compared at gene and pathway level. Immune cell composition was estimated through gene expression deconvolution analyses (TIDE). Results: Tumor mutational burden was similar between the two cohorts. At gene level, few genes had significantly different somatic mutation frequencies, or differential mRNA expression between AA and NonAA samples. Pathway level alterations showed inflammation, immunity (adaptive; innate), antigen presentation, and allograft rejection pathways were more affected by somatic mutations in AA samples. The affected genes differed from cancer to cancer and were not recurrent and therefore were missed at gene level analysis. Gene set enrichment and co-expression analysis also showed higher immune related pathway expression in AA samples. Unsupervised co-expression cluster analysis confirmed coordinated overexpression of genes involved in immunity, inflammation, and cytokine/chemokine signaling in AA patients. Two immunotherapy response predictive signatures, immune inflamed and the IFNG as well as sTILs score and PD-L1 positivity were also higher in AA samples. These findings raise the possibility that immune checkpoint inhibitors might be particularly effective in AA patients. In NonAA samples, the EMT transition, angiogenesis, adipogenesis, myogenesis, fatty acid metabolism, TGFβ signaling, UV-response, and hypoxia pathways were overexpressed. TIDE analysis suggested higher levels of TAM M2, overall TIDE score, and the Immune Exclusion score in NonAA samples. Conclusions: TNBC in AA patients more frequently harbor somatic mutations in genes involved with immune functions and overexpress immune and inflammatory genes compared to NonAA patients.

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

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1692 ◽  
Author(s):  
Jiande Wu ◽  
Tarun Karthik Kumar Mamidi ◽  
Lu Zhang ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Signaling Pathways ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Networks ◽  
Genome Wide Association Studies ◽  
Integrative Genomics ◽  
Gene Expression Variation ◽  
Expression Variation

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.

scholarly journals Whole Genome Transcriptome Analysis of the Association between Obesity and Triple-Negative Breast Cancer in Caucasian Women

2018 ◽  
Vol 15 (11) ◽  
pp. 2338 ◽  
Author(s):  
Tarun Mamidi ◽  
Jiande Wu ◽  
Paul Tchounwou ◽  
Lucio Miele ◽  
Chindo Hicks
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Signaling Pathways ◽  
Postmenopausal Women ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Normal Weight ◽  
Biological Pathways ◽  
Molecular Networks ◽  
Caucasian Women

Background: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, with poor outcomes. The molecular basis of TNBC remains poorly understood. The objective of this exploratory study was to investigate the association between obesity and TNBC in premenopausal and postmenopausal Caucasian women using transcription profiling. Methods: We compared gene expression levels of tumor samples drawn from normal weight, overweight, and obese pre and postmenopausal women diagnosed with TNBC. We performed hierarchical clustering to assess similarity in patterns of gene expression profiles, and conducted network and pathway analysis to identify molecular networks and biological pathways. Results: We discovered gene signatures distinguishing normal weight from obese, normal weight from overweight, and overweight from obese individuals in both premenopausal and postmenopausal women. The analysis revealed molecular networks and biological pathways associating obesity with TNBC. The discovered pathways included the unfolded protein response, endoplasmic reticulum stress, B cell receptor, and autophagy signaling pathways in obese premenopausal women; and the integrin, axonal guidance, ERK/MAPK (extracellular-signal-regulated kinase/mitogen activated protein kinase) and glutathione biosynthesis signaling pathways in obese postmenopausal women. Conclusions: The results suggest that both overweight and obese status are associated with TNBC, highlighting the need for conformation of these results in independent studies.

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