Journal Article
. 2019 Nov; 11(11):.
doi: 10.3390/cancers11111692.

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

Jiande Wu 1 Tarun Karthik Kumar Mamidi 2 Lu Zhang 3 Chindo Hicks 4 
  • PMID: 31683572
  •     64 References
  •     3 citations


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.

Keywords: epigenomic alterations; gene; genomic; mutation; triple-negative breast cancer.

Obesity and Triple-Negative Breast Cancer: Disparities, Controversies, and Biology.
Eric C Dietze, Tanya A Chavez, Victoria L Seewaldt.
Am J Pathol, 2017 Nov 13; 188(2). PMID: 29128565    Free PMC article.
Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: Preclinical investigation with the anti-p53 drug, PK11007.
Naoise C Synnott, Matthias R Bauer, +8 authors, Michael J Duffy.
Cancer Lett, 2017 Oct 27; 414. PMID: 29069577
Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency.
Masahito Kawazu, Shinya Kojima, +23 authors, Hiroyuki Mano.
PLoS Genet, 2017 Jun 22; 13(6). PMID: 28636652    Free PMC article.
Features of triple-negative breast cancer: Analysis of 38,813 cases from the national cancer database.
Magdalena L Plasilova, Brandon Hayse, +3 authors, Donald R Lannin.
Medicine (Baltimore), 2016 Sep 02; 95(35). PMID: 27583878    Free PMC article.
BRCA1 methylation: a significant role in tumour development?
Aurélie Catteau, Joanna R Morris.
Semin Cancer Biol, 2002 Aug 23; 12(5). PMID: 12191635
Molecular stratification of triple-negative breast cancers.
Charles M Perou.
Oncologist, 2010 Dec 16; 15 Suppl 5. PMID: 21138954
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
David Moher, Alessandro Liberati, +2 authors, PRISMA Group.
PLoS Med, 2009 Jul 22; 6(7). PMID: 19621072    Free PMC article.
Highly Cited.
Molecular features of triple negative breast cancer cells by genome-wide gene expression profiling analysis.
Masato Komatsu, Tetsuro Yoshimaru, +12 authors, Toyomasa Katagiri.
Int J Oncol, 2012 Dec 21; 42(2). PMID: 23254957
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
Alessandro Liberati, Douglas G Altman, +7 authors, David Moher.
PLoS Med, 2009 Jul 22; 6(7). PMID: 19621070    Free PMC article.
Highly Cited. Systematic Review.
Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome.
Robert Shoemaker, Jie Deng, Wei Wang, Kun Zhang.
Genome Res, 2010 Apr 27; 20(7). PMID: 20418490    Free PMC article.
Highly Cited.
A standardized framework for representation of ancestry data in genomics studies, with application to the NHGRI-EBI GWAS Catalog.
Joannella Morales, Danielle Welter, +15 authors, Jacqueline A L MacArthur.
Genome Biol, 2018 Feb 17; 19(1). PMID: 29448949    Free PMC article.
Highly Cited.
Germline Mutations in Triple-Negative Breast Cancer.
Eric Hahnen, Jan Hauke, +3 authors, Rita K Schmutzler.
Breast Care (Basel), 2017 Jun 15; 12(1). PMID: 28611536    Free PMC article.
Prognostic impact of PIK3CA protein expression in triple negative breast cancer and its subtypes.
C Elfgen, K Reeve, +5 authors, Z Varga.
J Cancer Res Clin Oncol, 2019 Jul 05; 145(8). PMID: 31270600
Systematic reviews of genetic association studies. Human Genome Epidemiology Network.
Gurdeep S Sagoo, Julian Little, Julian P T Higgins.
PLoS Med, 2009 Mar 06; 6(3). PMID: 19260758    Free PMC article.
Genome-wide association studies, field synopses, and the development of the knowledge base on genetic variation and human diseases.
Muin J Khoury, Lars Bertram, +25 authors, John P A Ioannidis.
Am J Epidemiol, 2009 Jun 06; 170(3). PMID: 19498075    Free PMC article.
Genetics of breast cancer: a topic in evolution.
S Shiovitz, L A Korde.
Ann Oncol, 2015 Jan 22; 26(7). PMID: 25605744    Free PMC article.
Highly Cited. Review.
Methylation of Breast Cancer Predisposition Genes in Early-Onset Breast Cancer: Australian Breast Cancer Family Registry.
Cameron M Scott, JiHoon Eric Joo, +6 authors, Melissa C Southey.
PLoS One, 2016 Dec 03; 11(11). PMID: 27902704    Free PMC article.
MUC4 overexpression augments cell migration and metastasis through EGFR family proteins in triple negative breast cancer cells.
Partha Mukhopadhyay, Imayavaramban Lakshmanan, +6 authors, Surinder K Batra.
PLoS One, 2013 Feb 15; 8(2). PMID: 23408941    Free PMC article.
Enduring epigenetic landmarks define the cancer microenvironment.
Ruth Pidsley, Mitchell G Lawrence, +26 authors, Susan J Clark.
Genome Res, 2018 Apr 14; 28(5). PMID: 29650553    Free PMC article.
Allelic expression imbalance polymorphisms in susceptibility chromosome regions and the risk and survival of breast cancer.
Wei Lin, Hong-Da Lin, +7 authors, Ze-Fang Ren.
Mol Carcinog, 2016 Apr 30; 56(1). PMID: 27128794
Epigenetics in cancer.
Manel Esteller.
N Engl J Med, 2008 Mar 14; 358(11). PMID: 18337604
Highly Cited. Review.
Differences in the mutational landscape of triple-negative breast cancer in African Americans and Caucasians.
Foluso O Ademuyiwa, Yu Tao, +2 authors, Cynthia X Ma.
Breast Cancer Res Treat, 2016 Dec 05; 161(3). PMID: 27915434    Free PMC article.
Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection.
Brian D Lehmann, Bojana Jovanović, +6 authors, Jennifer A Pietenpol.
PLoS One, 2016 Jun 17; 11(6). PMID: 27310713    Free PMC article.
Highly Cited.
limma powers differential expression analyses for RNA-sequencing and microarray studies.
Matthew E Ritchie, Belinda Phipson, +4 authors, Gordon K Smyth.
Nucleic Acids Res, 2015 Jan 22; 43(7). PMID: 25605792    Free PMC article.
Highly Cited.
Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up.
Hege O Ohnstad, Elin Borgen, +11 authors, Bjørn Naume.
Breast Cancer Res, 2017 Nov 16; 19(1). PMID: 29137653    Free PMC article.
Genetic susceptibility to triple-negative breast cancer.
Kristen N Stevens, Celine M Vachon, Fergus J Couch.
Cancer Res, 2013 Mar 29; 73(7). PMID: 23536562    Free PMC article.
Highly Cited. Review.
Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.
M Ashburner, C A Ball, +17 authors, G Sherlock.
Nat Genet, 2000 May 10; 25(1). PMID: 10802651    Free PMC article.
Highly Cited.
Epigenetic and genetic burden measures are associated with tumor characteristics in invasive breast carcinoma.
Dylan E O'Sullivan, Kevin C Johnson, +2 authors, Brock C Christensen.
Epigenetics, 2016 Apr 14; 11(5). PMID: 27070496    Free PMC article.
Upregulated expression of AT-rich interactive domain-containing protein 1B predicts poor prognosis in patients with triple-negative breast cancer.
Yan Cui, Xianan Bai, +3 authors, Da Pang.
Oncol Lett, 2019 Mar 15; 17(3). PMID: 30867762    Free PMC article.
An evaluation of processing methods for HumanMethylation450 BeadChip data.
Jie Liu, Kimberly D Siegmund.
BMC Genomics, 2016 Jun 24; 17. PMID: 27334613    Free PMC article.
Hypomethylation distinguishes genes of some human cancers from their normal counterparts.
A P Feinberg, B Vogelstein.
Nature, 1983 Jan 06; 301(5895). PMID: 6185846
Highly Cited.
Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer.
Jiande Wu, Tarun Karthik Kumar Mamidi, Lu Zhang, Chindo Hicks.
Int J Environ Res Public Health, 2019 Mar 27; 16(6). PMID: 30909550    Free PMC article.
International network of cancer genome projects.
International Cancer Genome Consortium, Thomas J Hudson, +413 authors, Huanming Yang.
Nature, 2010 Apr 16; 464(7291). PMID: 20393554    Free PMC article.
Highly Cited.
Outcome disparities in African American women with triple negative breast cancer: a comparison of epidemiological and molecular factors between African American and Caucasian women with triple negative breast cancer.
Lori A Sturtz, Jen Melley, +2 authors, Rachel E Ellsworth.
BMC Cancer, 2014 Feb 06; 14. PMID: 24495414    Free PMC article.
Whole exome sequencing of breast cancer (TNBC) cases from India: association of MSH6 and BRIP1 variants with TNBC risk and oxidative DNA damage.
M Aravind Kumar, Shaik Mohammad Naushad, +4 authors, M Lakshmi Narasu.
Mol Biol Rep, 2018 Aug 24; 45(5). PMID: 30136158
The Era of Multigene Panels Comes? The Clinical Utility of Oncotype DX and MammaPrint.
Ling Xin, Yin-Hua Liu, Tracey A Martin, Wen G Jiang.
World J Oncol, 2017 Nov 18; 8(2). PMID: 29147432    Free PMC article.
A novel BRCA1 germline mutation promotes triple-negative breast cancer cells progression and enhances sensitivity to DNA damage agents.
Kun Xu, Yaqin Shi, +3 authors, Xiaoxiang Guan.
Cancer Genet, 2019 Sep 03; 239. PMID: 31476665
The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.
Annalisa Buniello, Jacqueline A L MacArthur, +21 authors, Helen Parkinson.
Nucleic Acids Res, 2018 Nov 18; 47(D1). PMID: 30445434    Free PMC article.
Highly Cited.
Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response.
Esther H Lips, Magali Michaut, +11 authors, Center for Personalized Cancer Treatment.
Breast Cancer Res, 2015 Oct 05; 17(1). PMID: 26433948    Free PMC article.
Assessment of cumulative evidence on genetic associations: interim guidelines.
John P A Ioannidis, Paolo Boffetta, +14 authors, Muin J Khoury.
Int J Epidemiol, 2007 Sep 28; 37(1). PMID: 17898028
Highly Cited. Review.
Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.
Agnieszka K Witkiewicz, Sejin Chung, +4 authors, Erik S Knudsen.
Cell Rep, 2018 Feb 02; 22(5). PMID: 29386107    Free PMC article.
Standardized versus research-based PAM50 intrinsic subtyping of breast cancer.
A Prat, J S Parker.
Clin Transl Oncol, 2019 Aug 23; 22(6). PMID: 31435878
Identification of Genetic and Epigenetic Variants Associated with Breast Cancer Prognosis by Integrative Bioinformatics Analysis.
Arunima Shilpi, Yingtao Bi, +2 authors, Ramana V Davuluri.
Cancer Inform, 2017 Jan 18; 16. PMID: 28096648    Free PMC article.
DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid.
Krysta Mila Coyle, Cheryl A Dean, +4 authors, Paola Marcato.
Cancers (Basel), 2018 Oct 26; 10(11). PMID: 30352973    Free PMC article.
Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes.
Brian D Lehmann, Jennifer A Pietenpol.
J Pathol, 2013 Oct 12; 232(2). PMID: 24114677    Free PMC article.
Highly Cited. Review.
An evaluation of analysis pipelines for DNA methylation profiling using the Illumina HumanMethylation450 BeadChip platform.
Francesco Marabita, Malin Almgren, +8 authors, David Gomez-Cabrero.
Epigenetics, 2013 Feb 21; 8(3). PMID: 23422812    Free PMC article.
Highly Cited.
The Cancer Genome Atlas Pan-Cancer analysis project.
Cancer Genome Atlas Research Network, John N Weinstein, +7 authors, Joshua M Stuart.
Nat Genet, 2013 Sep 28; 45(10). PMID: 24071849    Free PMC article.
Highly Cited.
A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers.
Ashton C Berger, Anil Korkut, +46 authors, Rehan Akbani.
Cancer Cell, 2018 Apr 07; 33(4). PMID: 29622464    Free PMC article.
Highly Cited.
The clonal and mutational evolution spectrum of primary triple-negative breast cancers.
Sohrab P Shah, Andrew Roth, +56 authors, Samuel Aparicio.
Nature, 2012 Apr 13; 486(7403). PMID: 22495314    Free PMC article.
Highly Cited.
Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.
Kristen S Purrington, Susan Slager, +106 authors, Fergus J Couch.
Carcinogenesis, 2013 Dec 12; 35(5). PMID: 24325915    Free PMC article.
Highly Cited.
Common breast cancer susceptibility loci are associated with triple-negative breast cancer.
Kristen N Stevens, Celine M Vachon, +81 authors, Fergus J Couch.
Cancer Res, 2011 Aug 17; 71(19). PMID: 21844186    Free PMC article.
A systematic study of normalization methods for Infinium 450K methylation data using whole-genome bisulfite sequencing data.
Ting Wang, Weihua Guan, +5 authors, Wei Chen.
Epigenetics, 2015 Jun 04; 10(7). PMID: 26036609    Free PMC article.
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.
Fergus J Couch, Steven N Hart, +38 authors, Peter A Fasching.
J Clin Oncol, 2014 Dec 03; 33(4). PMID: 25452441    Free PMC article.
Highly Cited.
DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine.
Jia Yu, Bo Qin, +19 authors, Liewei Wang.
J Clin Invest, 2018 May 01; 128(6). PMID: 29708513    Free PMC article.
AHNAK suppresses tumour proliferation and invasion by targeting multiple pathways in triple-negative breast cancer.
Bo Chen, Jin Wang, +7 authors, Xiaoming Xie.
J Exp Clin Cancer Res, 2017 May 13; 36(1). PMID: 28494797    Free PMC article.
An Integrative Genomics Approach for Associating GWAS Information with Triple-Negative Breast Cancer.
Chindo Hicks, Ranjit Kumar, +4 authors, Lucio Miele.
Cancer Inform, 2013 Feb 21; 12. PMID: 23423317    Free PMC article.
Epigenetic silencing of triple negative breast cancer hallmarks by Withaferin A.
Katarzyna Szarc Vel Szic, Ken Declerck, +4 authors, Wim Vanden Berghe.
Oncotarget, 2017 May 04; 8(25). PMID: 28467815    Free PMC article.
SWAN: Subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips.
Jovana Maksimovic, Lavinia Gordon, Alicia Oshlack.
Genome Biol, 2012 Jun 19; 13(6). PMID: 22703947    Free PMC article.
Highly Cited.
A Review of the Hereditary Component of Triple Negative Breast Cancer: High- and Moderate-Penetrance Breast Cancer Genes, Low-Penetrance Loci, and the Role of Nontraditional Genetic Elements.
Darrell L Ellsworth, Clesson E Turner, Rachel E Ellsworth.
J Oncol, 2019 Aug 06; 2019. PMID: 31379942    Free PMC article.
Identification of novel prognostic indicators for triple-negative breast cancer patients through integrative analysis of cancer genomics data and protein interactome data.
Fan Zhang, Chunyan Ren, +6 authors, Martin J Walsh.
Oncotarget, 2016 Oct 01; 7(44). PMID: 27690302    Free PMC article.
Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers.
Bernardo P de Almeida, Joana Dias Apolónio, Alexandra Binnie, Pedro Castelo-Branco.
BMC Cancer, 2019 Mar 15; 19(1). PMID: 30866861    Free PMC article.
Patterns of Mutation Enrichment in Metastatic Triple-Negative Breast Cancer.
César H Saravia, Claudio Flores, +5 authors, Joseph A Pinto.
Clin Med Insights Oncol, 2019 Aug 27; 13. PMID: 31447598    Free PMC article.
Triple-negative breast cancer in African-American women: disparities versus biology.
Eric C Dietze, Christopher Sistrunk, +2 authors, Victoria L Seewaldt.
Nat Rev Cancer, 2015 Feb 13; 15(4). PMID: 25673085    Free PMC article.
Highly Cited. Review.
DNA Methylation Patterns in Normal Tissue Correlate more Strongly with Breast Cancer Status than Copy-Number Variants.
Yang Gao, Martin Widschwendter, Andrew E Teschendorff.
EBioMedicine, 2018 May 08; 31. PMID: 29735413    Free PMC article.
Molecular and Clinical Relevance of ZBTB38 Expression Levels in Prostate Cancer.
Maud de Dieuleveult, Claire Marchal, +2 authors, Benoit Miotto.
Cancers (Basel), 2020 May 06; 12(5). PMID: 32365491    Free PMC article.
Unraveling the Genomic-Epigenomic Interaction Landscape in Triple Negative and Non-Triple Negative Breast Cancer.
Jiande Wu, Tarun Karthik Kumar Mamidi, Lu Zhang, Chindo Hicks.
Cancers (Basel), 2020 Jun 18; 12(6). PMID: 32545594    Free PMC article.
Elucidation of the Genomic-Epigenomic Interaction Landscape of Aggressive Prostate Cancer.
Tarun Karthik Kumar Mamidi, Jiande Wu, Chindo Hicks.
Biomed Res Int, 2021 Jan 30; 2021. PMID: 33511206    Free PMC article.