{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T03:26:02Z","timestamp":1768015562703,"version":"3.49.0"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"ARC DECRA","award":["200100200"],"award-info":[{"award-number":["200100200"]}]},{"name":"Australian Government Research Training Program (RTP) Scholarship and the Vice Chancellor & President\u2019s Scholarship offered by the University of South Australia"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Identifying meaningful cancer driver genes in a cohort of tumors is a challenging task in cancer genomics. Although existing studies have identified known cancer drivers, most of them focus on detecting coding drivers with mutations. It is acknowledged that non-coding drivers can regulate driver mutations to promote cancer growth. In this work, we propose a novel node importance-based network analysis (NIBNA) framework to detect coding and non-coding cancer drivers. We hypothesize that cancer drivers are crucial to the formation of community structures in cancer network, and removing them from the network greatly perturbs the network structure thereby critically affecting the functioning of the network. NIBNA detects cancer drivers using a three-step process: first, a condition-specific network is built by incorporating gene expression data and gene networks; second, the community structures in the network are estimated; and third, a centrality-based metric is applied to compute node importance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We apply NIBNA to the BRCA dataset, and it outperforms existing state-of-art methods in detecting coding cancer drivers. NIBNA also predicts 265 miRNA drivers, and majority of these drivers have been validated in literature. Further we apply NIBNA to detect cancer subtype-specific drivers, and several predicted drivers have been validated to be associated with cancer subtypes. Lastly, we evaluate NIBNA\u2019s performance in detecting epithelial\u2013mesenchymal transition drivers, and we confirmed 8 coding and 13 miRNA drivers in the list of known genes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The source code can be accessed at https:\/\/github.com\/mandarsc\/NIBNA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btab145","type":"journal-article","created":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T12:09:20Z","timestamp":1614514160000},"page":"2521-2528","source":"Crossref","is-referenced-by-count":14,"title":["NIBNA: a network-based node importance approach for identifying breast cancer drivers"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1687-2471","authenticated-orcid":false,"given":"Mandar S.","family":"Chaudhary","sequence":"first","affiliation":[{"name":"Infinia ML , Durham, NC 27560, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8884-3584","authenticated-orcid":false,"given":"Vu V.H.","family":"Pham","sequence":"additional","affiliation":[{"name":"UniSA STEM University of South Australia , Mawson Lakes, SA 5095, Australia"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9732-4313","authenticated-orcid":false,"given":"Thuc D.","family":"Le","sequence":"additional","affiliation":[{"name":"UniSA STEM University of South Australia , Mawson Lakes, SA 5095, Australia"}]}],"member":"286","published-online":{"date-parts":[[2021,3,2]]},"reference":[{"key":"2023051609213699400_btab145-B1","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1093\/bioinformatics\/btl039","article-title":"Cfinder: locating cliques and overlapping modules in biological networks","volume":"22","author":"Adamcsek","year":"2006","journal-title":"Bioinformatics"},{"key":"2023051609213699400_btab145-B2","doi-asserted-by":"crossref","first-page":"e05005","DOI":"10.7554\/eLife.05005","article-title":"Predicting effective microRNA target sites in mammalian mRNAs","volume":"4","author":"Agarwal","year":"2015","journal-title":"elife"},{"key":"2023051609213699400_btab145-B3","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10549-017-4202-z","article-title":"Tumour suppressor ep300, a modulator of paclitaxel resistance and stemness, is downregulated in metaplastic breast cancer","volume":"163","author":"Asaduzzaman","year":"2017","journal-title":"Breast Cancer Res. Treat"},{"key":"2023051609213699400_btab145-B4","doi-asserted-by":"crossref","first-page":"R124","DOI":"10.1186\/gb-2012-13-12-r124","article-title":"Drivernet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer","volume":"13","author":"Bashashati","year":"2012","journal-title":"Genome Biol"},{"key":"2023051609213699400_btab145-B5","doi-asserted-by":"crossref","first-page":"P10008","DOI":"10.1088\/1742-5468\/2008\/10\/P10008","article-title":"Fast unfolding of communities in large networks","volume":"2008","author":"Blondel","year":"2008","journal-title":"J. Stat. Mech. Theory Exp"},{"key":"2023051609213699400_btab145-B6","doi-asserted-by":"crossref","first-page":"056114","DOI":"10.1103\/PhysRevE.80.056114","article-title":"Spectral properties of networks with community structure","volume":"80","author":"Chauhan","year":"2009","journal-title":"Phys. Rev. E"},{"key":"2023051609213699400_btab145-B7","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1210\/me.2010-0368","article-title":"JunD and junB integrate prostaglandin e2 activation of breast cancer-associated proximal aromatase promoters","volume":"25","author":"Chen","year":"2011","journal-title":"Mol. Endocrinol"},{"key":"2023051609213699400_btab145-B8","doi-asserted-by":"crossref","first-page":"D239","DOI":"10.1093\/nar\/gkv1258","article-title":"miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database","volume":"44","author":"Chou","year":"2016","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"2023051609213699400_btab145-B9","first-page":"77","volume":"7"},{"key":"2023051609213699400_btab145-B10","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cels.2018.05.019","article-title":"Combinatorial targeting by micrornas co-ordinates post-transcriptional control of EMT","volume":"7","author":"Cursons","year":"2018","journal-title":"Cell Syst"},{"key":"2023051609213699400_btab145-B11","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/nmeth.3485","article-title":"miRWalk2.0: a comprehensive atlas of microRNA-target interactions","volume":"12","author":"Dweep","year":"2015","journal-title":"Nat. Methods"},{"key":"2023051609213699400_btab145-B12","doi-asserted-by":"crossref","first-page":"D805","DOI":"10.1093\/nar\/gku1075","article-title":"Cosmic: exploring the world\u2019s knowledge of somatic mutations in human cancer","volume":"43","author":"Forbes","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023051609213699400_btab145-B13","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nrc1299","article-title":"A census of human cancer genes","volume":"4","author":"Futreal","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"2023051609213699400_btab145-B14","doi-asserted-by":"crossref","first-page":"D258","DOI":"10.1093\/nar\/gkh036","article-title":"The gene ontology (go) database and informatics resource","volume":"32","year":"2004","journal-title":"Nucleic Acids Res"},{"key":"2023051609213699400_btab145-B15","doi-asserted-by":"crossref","first-page":"e169","DOI":"10.1093\/nar\/gks743","article-title":"Functional impact bias reveals cancer drivers","volume":"40","author":"Gonzalez-Perez","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2023051609213699400_btab145-B16","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/ncb1722","article-title":"The mir-200 family and mir-205 regulate epithelial to mesenchymal transition by targeting zeb1 and sip1","volume":"10","author":"Gregory","year":"2008","journal-title":"Nat. Cell Biol"},{"key":"2023051609213699400_btab145-B17","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1002\/wics.1319","article-title":"Community detection in large-scale networks: a survey and empirical evaluation","volume":"6","author":"Harenberg","year":"2014","journal-title":"Wiley Interdiscip. Rev. Comput. Stat"},{"key":"2023051609213699400_btab145-B18","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/sj.bjc.6603616","article-title":"Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients","volume":"96","author":"Hinnis","year":"2007","journal-title":"Br. J. Cancer"},{"key":"2023051609213699400_btab145-B19","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nmeth.4514","article-title":"NetSig: network-based discovery from cancer genomes","volume":"15","author":"Horn","year":"2018","journal-title":"Nat. Methods"},{"key":"2023051609213699400_btab145-B20","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13073-014-0056-8","article-title":"DawnRank: discovering personalized driver genes in cancer","volume":"6","author":"Hou","year":"2014","journal-title":"Genome Med"},{"key":"2023051609213699400_btab145-B21","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.15252\/embr.201439392","article-title":"E2f1 induces mir-224\/452 expression to drive EMT through txnip downregulation","volume":"15","author":"Knoll","year":"2014","journal-title":"EMBO Rep"},{"key":"2023051609213699400_btab145-B22","doi-asserted-by":"crossref","first-page":"S21","DOI":"10.1093\/annonc\/12.suppl_1.S21","article-title":"Modulation of p27\/cdk2 complex formation through 4d5-mediated inhibition of her2 receptor signaling","volume":"12","author":"Lane","year":"2001","journal-title":"Ann. Oncol"},{"key":"2023051609213699400_btab145-B23","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/nature12213","article-title":"Mutational heterogeneity in cancer and the search for new cancer-associated genes","volume":"499","author":"Lawrence","year":"2013","journal-title":"Nature"},{"key":"2023051609213699400_btab145-B24","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/bjc.2014.556","article-title":"Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in her2-positive breast cancer","volume":"112","author":"Lee","year":"2015","journal-title":"Br. J. Cancer"},{"key":"2023051609213699400_btab145-B25","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.1038\/s41388-017-0114-y","article-title":"Fyn promotes mesenchymal phenotypes of basal type breast cancer cells through stat5\/notch2 signaling node","volume":"37","author":"Lee","year":"2018","journal-title":"Oncogene"},{"key":"2023051609213699400_btab145-B26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/npjbcancer.2015.23","article-title":"Pam50 gene signatures and breast cancer prognosis with adjuvant anthracycline-and taxane-based chemotherapy: correlative analysis of c9741 (alliance)","volume":"2","author":"Liu","year":"2016","journal-title":"NPJ Breast Cancer"},{"key":"2023051609213699400_btab145-B27","doi-asserted-by":"crossref","first-page":"738","DOI":"10.7150\/ijms.24981","article-title":"The suppression of dusp5 expression correlates with paclitaxel resistance and poor prognosis in basal-like breast cancer","volume":"15","author":"Liu","year":"2018","journal-title":"Int. J. Med. Sci"},{"key":"2023051609213699400_btab145-B28","doi-asserted-by":"crossref","first-page":"D737","DOI":"10.1093\/nar\/gkw995","article-title":"Update of the FANTOM web resource: high resolution transcriptome of diverse cell types in mammals","volume":"45","author":"Lizio","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023051609213699400_btab145-B29","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1172\/JCI44745","article-title":"The jak2\/stat3 signaling pathway is required for growth of cd44+ cd24\u2013stem cell\u2013like breast cancer cells in human tumors","volume":"121","author":"Marotta","year":"2011","journal-title":"J. Clin. Invest"},{"key":"2023051609213699400_btab145-B30","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/carcin\/bgl091","article-title":"Impact of constitutive igf1\/igf2 stimulation on the transcriptional program of human breast cancer cells","volume":"28","author":"Pacher","year":"2007","journal-title":"Carcinogenesis"},{"key":"2023051609213699400_btab145-B31","author":"Page","year":"1998"},{"key":"2023051609213699400_btab145-B32","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1056\/NEJMoa041588","article-title":"A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer","volume":"351","author":"Paik","year":"2004","journal-title":"N. Engl. J. Med"},{"key":"2023051609213699400_btab145-B33","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1101\/gad.1640608","article-title":"The mir-200 family determines the epithelial phenotype of cancer cells by targeting the e-cadherin repressors zeb1 and zeb2","volume":"22","author":"Park","year":"2008","journal-title":"Genes Dev"},{"key":"2023051609213699400_btab145-B34","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1200\/JCO.2008.18.1370","article-title":"Supervised risk predictor of breast cancer based on intrinsic subtypes","volume":"27","author":"Parker","year":"2009","journal-title":"J. Clin. Oncol"},{"key":"2023051609213699400_btab145-B35","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/S0959-8049(05)80137-6","article-title":"Plasma insulin-like growth factor-1 (igf-1) concentrations in human breast cancer","volume":"29","author":"Peyrat","year":"1993","journal-title":"Eur. J. Cancer"},{"key":"2023051609213699400_btab145-B36","doi-asserted-by":"crossref","first-page":"e1007538","DOI":"10.1371\/journal.pcbi.1007538","article-title":"CBNA: a control theory based method for identifying coding and non-coding cancer drivers","volume":"15","author":"Pham","year":"2019","journal-title":"PLoS Comput. Biol"},{"key":"2023051609213699400_btab145-B37","doi-asserted-by":"crossref","first-page":"8347","DOI":"10.1158\/0008-5472.CAN-09-4149","article-title":"Cdc42-interacting protein 4 promotes breast cancer cell invasion and formation of invadopodia through activation of n-wasp","volume":"70","author":"Pichot","year":"2010","journal-title":"Cancer Res"},{"key":"2023051609213699400_btab145-B38","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/msb.2012.68","article-title":"Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers","volume":"9","author":"Reimand","year":"2013","journal-title":"Mol. Syst. Biol"},{"key":"2023051609213699400_btab145-B39","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1023\/B:BREA.0000032926.74216.7d","article-title":"Differential gene expression of TGF\u03b2 inducible early gene (tieg), smad7, smad2 and bard1 in normal and malignant breast tissue","volume":"86","author":"Reinholz","year":"2004","journal-title":"Breast Cancer Res. Treat"},{"key":"2023051609213699400_btab145-B40","doi-asserted-by":"crossref","first-page":"094102","DOI":"10.1103\/PhysRevLett.97.094102","article-title":"Characterizing the dynamical importance of network nodes and links","volume":"97","author":"Restrepo","year":"2006","journal-title":"Phys. Rev. Lett"},{"key":"2023051609213699400_btab145-B41","author":"Ring","year":"2020"},{"key":"2023051609213699400_btab145-B42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12864-019-5887-7","article-title":"Refinement of breast cancer molecular classification by miRNA expression profiles","volume":"20","author":"S\u00f8kilde","year":"2019","journal-title":"BMC Genomics"},{"key":"2023051609213699400_btab145-B43","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1093\/jnci\/djj052","article-title":"Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis","volume":"98","author":"Sotiriou","year":"2006","journal-title":"J. Natl. Cancer Inst"},{"key":"2023051609213699400_btab145-B44","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/sam.10100","article-title":"Complex networks as a unified framework for descriptive analysis and predictive modeling in climate science","volume":"4","author":"Steinhaeuser","year":"2011","journal-title":"Stat. Anal. Data Min. ASA Data Sci. J"},{"key":"2023051609213699400_btab145-B45","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1093\/bioinformatics\/btt395","article-title":"OncodriveCLUST: exploiting the positional clustering of somatic mutations to identify cancer genes","volume":"29","author":"Tamborero","year":"2013","journal-title":"Bioinformatics"},{"key":"2023051609213699400_btab145-B46","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.15252\/emmm.201404208","article-title":"Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients","volume":"6","author":"Tan","year":"2014","journal-title":"EMBO Mol. Med"},{"key":"2023051609213699400_btab145-B47","doi-asserted-by":"crossref","first-page":"W556","DOI":"10.1093\/nar\/gkz430","article-title":"Gepia2: an enhanced web server for large-scale expression profiling and interactive analysis","volume":"47","author":"Tang","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023051609213699400_btab145-B48","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/415530a","article-title":"Gene expression profiling predicts clinical outcome of breast cancer","volume":"415","author":"van't Veer","year":"2002","journal-title":"Nature"},{"key":"2023051609213699400_btab145-B49","doi-asserted-by":"crossref","first-page":"rs8","DOI":"10.1126\/scisignal.2001699","article-title":"A directed protein interaction network for investigating intracellular signal transduction","volume":"4","author":"Vinayagam","year":"2011","journal-title":"Sci. Signaling"},{"key":"2023051609213699400_btab145-B50","doi-asserted-by":"crossref","first-page":"4976","DOI":"10.1073\/pnas.1603992113","article-title":"Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets","volume":"113","author":"Vinayagam","year":"2016","journal-title":"Proc. Natl. Acad. Sci"},{"key":"2023051609213699400_btab145-B51","doi-asserted-by":"crossref","first-page":"D153","DOI":"10.1093\/nar\/gku1215","article-title":"DIANA-TarBase v7. 0: indexing more than half a million experimentally supported miRNA: mRNA interactions","volume":"43","author":"Vlachos","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023051609213699400_btab145-B52","doi-asserted-by":"crossref","first-page":"D119","DOI":"10.1093\/nar\/gkp803","article-title":"TransmiR: a transcription factor\u2013microRNA regulation database","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"2023051609213699400_btab145-B53","article-title":"Identifying and characterizing nodes important to community structure using the spectrum of the graph","volume":"6, e27418","author":"Wang","year":"2011","journal-title":"PLoS One"},{"key":"2023051609213699400_btab145-B54","first-page":"7880","article-title":"Bioinformatics analysis of gene expression profiles to identify causal genes in luminal B2 breast cancer","volume":"14","author":"Wang","year":"2017","journal-title":"Oncol. Lett"},{"key":"2023051609213699400_btab145-B55","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The cancer genome atlas pan-cancer analysis project","volume":"45","author":"Weinstein","year":"2013","journal-title":"Nat. Genet"},{"key":"2023051609213699400_btab145-B56","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1093\/bioinformatics\/btx627","article-title":"OncomiR: an online resource for exploring pan-cancer microRNA dysregulation","volume":"34","author":"Wong","year":"2018","journal-title":"Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btab145\/39301318\/btab145.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/17\/2521\/50339325\/btab145.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/17\/2521\/50339325\/btab145.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T09:27:05Z","timestamp":1684229225000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/37\/17\/2521\/6156790"}},"subtitle":[],"editor":[{"family":"Peter Robinson","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2021,3,2]]},"references-count":56,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2021,9,9]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btab145","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,9,1]]},"published":{"date-parts":[[2021,3,2]]}}}