{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T17:38:13Z","timestamp":1757612293221,"version":"3.44.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council of Taiwan","doi-asserted-by":"publisher","award":["NSTC 113\u20132221-E-003-015","NSTC 114\u20132221-E-003-019"],"award-info":[{"award-number":["NSTC 113\u20132221-E-003-015","NSTC 114\u20132221-E-003-019"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We introduce consensus MSClustering, an unsupervised hierarchical network approach that integrates multi-omics data to identify molecular subtypes and conserved pathways across diverse cancers. Using a novel heterogeneity index, we selected 167 key genes with functionally coherent roles validated through Gene Ontology analysis. Applied to 2439 tumors spanning 10 cancer types\u2014and successfully extended to 2675 tumors (12 types) including cases with incomplete molecular data\u2014MSClustering demonstrated: (i) precise classification of major cancer types and breast cancer molecular subtypes; (ii) discovery of novel pan-cancer squamous metaplastic signatures; (iii) exceptional prognostic stratification (log-rank P\u2009=\u20092.3\u2009\u00d7\u200910\u221246); and (iv) superior performance over existing methods (COCA\/SNF) in classification accuracy, cluster robustness, and computational efficiency. The method\u2019s multi-scale architecture uniquely resolves breast cancer heterogeneity across biological resolution levels. Pathway analysis further revealed four key oncogenic programs\u2014proteoglycan signaling, chromosomal stability, VEGF-mediated angiogenesis, and drug metabolism\u2014along with disruptions in immune and digestive system functions. This integrative framework marks a significant advancement in cancer genomics by enabling more refined molecular classification, enhanced prognostic insights, and deeper understanding of disease mechanisms. These results highlight the potential of MSClustering to inform the development of clinically relevant biomarkers and support more personalized strategies in precision oncology.<\/jats:p>","DOI":"10.1093\/bib\/bbaf452","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T11:19:09Z","timestamp":1755515949000},"source":"Crossref","is-referenced-by-count":0,"title":["Mapping cancer heterogeneity: a consensus network approach to subtypes and pathways"],"prefix":"10.1093","volume":"26","author":[{"given":"Geng-Ming","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Physics, National Taiwan Normal University , 88 Sec.4 Ting-Chou Rd., Taipei 116 ,","place":["Taiwan"]}]},{"given":"Hsin-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physics, National Taiwan Normal University , 88 Sec.4 Ting-Chou Rd., Taipei 116 ,","place":["Taiwan"]}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2202-2318","authenticated-orcid":false,"given":"Chi-Ming","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physics, National Taiwan Normal University , 88 Sec.4 Ting-Chou Rd., Taipei 116 ,","place":["Taiwan"]}]}],"member":"286","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"2025090405302592500_ref1","doi-asserted-by":"publisher","first-page":"e70001","DOI":"10.1111\/cts.70001","article-title":"From organs to algorithms: redefining cancer classification in the age of artificial intelligence","volume":"17","author":"Khozin","year":"2024","journal-title":"Clin Transl Sci"},{"key":"2025090405302592500_ref2","doi-asserted-by":"publisher","first-page":"70","DOI":"10.32074\/1591-951X-213","article-title":"The 2020 WHO classification of soft tissue tumours: news and perspectives","volume":"113","author":"Sbaraglia","year":"2021","journal-title":"Pathologica."},{"key":"2025090405302592500_ref3","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1126\/science.286.5439.531","article-title":"Molecular classification of cancer: class discovery and class prediction by gene expression monitoring","volume":"286","author":"Golub","year":"1999","journal-title":"Science."},{"key":"2025090405302592500_ref4","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/35021093","article-title":"Molecular portraits of human breast tumours","volume":"406","author":"Perou","year":"2000","journal-title":"Nature."},{"key":"2025090405302592500_ref5","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/j.cell.2014.06.049","article-title":"Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin","volume":"158","author":"Hoadley","year":"2014","journal-title":"Cell."},{"key":"2025090405302592500_ref6","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-origin patterns dominate the molecular classification of 10,000 Tumors from 33 types of cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell."},{"key":"2025090405302592500_ref7","first-page":"59","article-title":"Applications of machine learning in cancer prediction and prognosis","volume":"2","author":"Cruz","year":"2007","journal-title":"Cancer informatics"},{"key":"2025090405302592500_ref8","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/nature21056","article-title":"Dermatologist-level classification of skin cancer with deep neural networks","volume":"542","author":"Esteva","year":"2017","journal-title":"Nature."},{"key":"2025090405302592500_ref9","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1158\/1078-0432.CCR-17-0853","article-title":"Deep learning-based multi-omics integration robustly predicts survival in liver cancer","volume":"24","author":"Chaudhary","year":"2018","journal-title":"Clinical cancer research : an official journal of the American Association for Cancer Research"},{"key":"2025090405302592500_ref10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.csbj.2014.11.005","article-title":"Machine learning applications in cancer prognosis and prediction","volume":"13","author":"Kourou","year":"2015","journal-title":"Comput Struct Biotechnol J"},{"key":"2025090405302592500_ref11","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1186\/1471-2105-15-308","article-title":"Distinguishing between driver and passenger mutations in individual cancer genomes by network enrichment analysis","volume":"15","author":"Merid","year":"2014","journal-title":"BMC Bioinformatics"},{"key":"2025090405302592500_ref12","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformatics."},{"key":"2025090405302592500_ref13","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1093\/bioinformatics\/btt019","article-title":"CluePedia Cytoscape plugin: pathway insights using integrated experimental and in silico data","volume":"29","author":"Bindea","year":"2013","journal-title":"Bioinformatics."},{"key":"2025090405302592500_ref14","doi-asserted-by":"publisher","first-page":"e29233","DOI":"10.1002\/jmv.29233","article-title":"Unraveling the evolutionary patterns and phylogenomics of coronaviruses: a consensus network approach","volume":"95","author":"Hu","year":"2023","journal-title":"J Med Virol"},{"key":"2025090405302592500_ref15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/01652176.2025.2465570","article-title":"Phylogenetic network of infectious bronchitis virus: exploring the impact of migratory birds on viral clustering, evolution, and recombination","volume":"45","author":"Tai","year":"2025","journal-title":"Vet Q"},{"key":"2025090405302592500_ref16","doi-asserted-by":"publisher","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"2025090405302592500_ref17","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.cell.2011.07.014","article-title":"A ceRNA hypothesis: the Rosetta stone of a hidden RNA language?","volume":"146","author":"Salmena","year":"2011","journal-title":"Cell."},{"key":"2025090405302592500_ref18","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1016\/j.gendis.2021.03.009","article-title":"The pseudogenes of eukaryotic translation elongation factors (EEFs): role in cancer and other human diseases","volume":"9","author":"Cristiano","year":"2022","journal-title":"Genes & Diseases"},{"key":"2025090405302592500_ref19","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1093\/jmcb\/mjv014","article-title":"Ribosomal proteins: functions beyond the ribosome","volume":"7","author":"Zhou","year":"2015","journal-title":"J Mol Cell Biol"},{"key":"2025090405302592500_ref20","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1186\/s12885-018-4178-z","article-title":"Diagnostic and prognostic implications of ribosomal protein transcript expression patterns in human cancers","volume":"18","author":"Dolezal","year":"2018","journal-title":"BMC Cancer"},{"key":"2025090405302592500_ref21","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1097\/PPO.0000000000000638","article-title":"Gene expression profiles in cancers and their therapeutic implications","volume":"29","author":"Creighton","year":"2023","journal-title":"Cancer journal (Sudbury, Mass)"},{"key":"2025090405302592500_ref22","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/nmeth.2810","article-title":"Similarity network fusion for aggregating data types on a genomic scale","volume":"11","author":"Wang","year":"2014","journal-title":"Nat Methods"},{"key":"2025090405302592500_ref23","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","article-title":"ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking","volume":"26","author":"Wilkerson","year":"2010","journal-title":"Bioinformatics."},{"key":"2025090405302592500_ref24","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1016\/0092-8674(90)90186-I","article-title":"A genetic model for colorectal tumorigenesis","volume":"61","author":"Fearon","year":"1990","journal-title":"Cell."},{"key":"2025090405302592500_ref25","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1159\/000151398","article-title":"Keratinizing squamous metaplasia of the bladder: a review","volume":"81","author":"Ahmad","year":"2008","journal-title":"Urol Int"},{"key":"2025090405302592500_ref26","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1590\/1806-9282.62.07.618","article-title":"Metaplastic squamous cell carcinoma of the breast: a case report and literature review","volume":"62","author":"Graziano","year":"2016","journal-title":"Revista da Associacao Medica Brasileira"},{"key":"2025090405302592500_ref27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11882-024-01181-7","article-title":"Mechanisms of bone morphogenetic protein 2 in respiratory diseases","volume":"25","author":"Wen","year":"2024","journal-title":"Curr Allergy Asthma Rep"},{"key":"2025090405302592500_ref28","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1080\/01926230601059969","article-title":"Respiratory tract lesions in noninhalation studies","volume":"35","author":"Sells","year":"2007","journal-title":"Toxicol Pathol"},{"key":"2025090405302592500_ref29","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nrc.2017.68","article-title":"Metaplasia: tissue injury adaptation and a precursor to the dysplasia\u2013cancer sequence","volume":"17","author":"Giroux","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"2025090405302592500_ref30","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1097\/JTO.0b013e318206a221","article-title":"International association for the study of lung cancer\/american thoracic society\/european respiratory society international multidisciplinary classification of lung adenocarcinoma","volume":"6","author":"Travis","year":"2011","journal-title":"Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer"},{"key":"2025090405302592500_ref31","doi-asserted-by":"publisher","first-page":"32","DOI":"10.5858\/arpa.2012-0033-OA","article-title":"Validation of interobserver agreement in lung cancer assessment: Hematoxylin-eosin diagnostic reproducibility for non\u2013small cell lung cancer: the 2004 World Health Organization classification and therapeutically relevant subsets","volume":"137","author":"Grilley-Olson","year":"2012","journal-title":"Arch Pathol Lab Med"},{"key":"2025090405302592500_ref32","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/S1470-2045(10)70008-5","article-title":"Breast cancer molecular profiling with single sample predictors: a retrospective analysis","volume":"11","author":"Weigelt","year":"2010","journal-title":"Lancet Oncol"},{"key":"2025090405302592500_ref33","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/s41571-020-0340-z","article-title":"Lineage plasticity in cancer: a shared pathway of therapeutic resistance","volume":"17","author":"Quintanal-Villalonga","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"2025090405302592500_ref34","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9070791","article-title":"Roles of XBP1s in transcriptional regulation of target genes","volume":"9","author":"Park","year":"2021","journal-title":"Biomedicines."},{"key":"2025090405302592500_ref35","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s10911-020-09443-6","article-title":"The novel transcription factor CREB3L4 contributes to the progression of human breast carcinoma","volume":"25","author":"Pu","year":"2020","journal-title":"J Mammary Gland Biol Neoplasia"},{"key":"2025090405302592500_ref36","doi-asserted-by":"publisher","first-page":"115335","DOI":"10.1016\/j.biopha.2023.115335","article-title":"Regulatory mechanisms of the cAMP-responsive element binding protein 3 (CREB3) family in cancers","volume":"166","author":"Yuxiong","year":"2023","journal-title":"Biomed Pharmacother"},{"key":"2025090405302592500_ref37","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13143557","article-title":"TBC1D9: an important modulator of tumorigenesis in breast cancer","volume":"13","author":"Kothari","year":"2021","journal-title":"Cancers."},{"key":"2025090405302592500_ref38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41540-021-00169-7","article-title":"Inference of phenotype-relevant transcriptional regulatory networks elucidates cancer type-specific regulatory mechanisms in a pan-cancer study","volume":"7","author":"Emad","year":"2021","journal-title":"npj Systems Biology and Applications"},{"key":"2025090405302592500_ref39","doi-asserted-by":"publisher","first-page":"39513","DOI":"10.1074\/jbc.M112.405050","article-title":"Hyperactivity of the Ero1\u03b1 oxidase elicits endoplasmic reticulum stress but no broad antioxidant response","volume":"287","author":"Hansen","year":"2012","journal-title":"J Biol Chem"},{"key":"2025090405302592500_ref40","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1038\/s41598-023-28355-z","article-title":"CENPF knockdown inhibits adriamycin chemoresistance in triple-negative breast cancer via the Rb-E2F1 axis","volume":"13","author":"Wang","year":"2023","journal-title":"Sci Rep"},{"key":"2025090405302592500_ref41","doi-asserted-by":"publisher","first-page":"4767","DOI":"10.1038\/onc.2013.422","article-title":"Novel role of engrailed 1 as a prosurvival transcription factor in basal-like breast cancer and engineering of interference peptides block its oncogenic function","volume":"33","author":"Beltran","year":"2014","journal-title":"Oncogene."},{"key":"2025090405302592500_ref42","doi-asserted-by":"publisher","DOI":"10.1093\/ijnp\/pyae040","article-title":"Upregulation of phosphodiesterase 7A contributes to concurrent pain and depression via inhibition of cAMP-PKA-CREB-BDNF Signaling and neuroinflammation in the hippocampus of mice","volume":"27","author":"Chen","year":"2024","journal-title":"Int J Neuropsychopharmacol"},{"key":"2025090405302592500_ref43","doi-asserted-by":"publisher","first-page":"e7394","DOI":"10.1002\/cam4.7394","article-title":"Impact of genomic and epigenomic alterations of multigene on a multicancer pedigree","volume":"13","author":"Gao","year":"2024","journal-title":"Cancer Med"},{"key":"2025090405302592500_ref44","doi-asserted-by":"publisher","first-page":"23171","DOI":"10.1038\/srep23171","article-title":"Proteasome activators, PA28\u03b3 and PA200, play indispensable roles in male fertility","volume":"6","author":"Huang","year":"2016","journal-title":"Sci Rep"},{"key":"2025090405302592500_ref45","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1038\/s41594-020-00541-x","article-title":"Stepwise gating of the Sec61 protein-conducting channel by Sec63 and Sec62","volume":"28","author":"Itskanov","year":"2021","journal-title":"Nat Struct Mol Biol"},{"key":"2025090405302592500_ref46","doi-asserted-by":"publisher","first-page":"101524","DOI":"10.1016\/j.jbc.2021.101524","article-title":"RNA-binding protein RBM28 can translocate from the nucleolus to the nucleoplasm to inhibit the transcriptional activity of p53","volume":"298","author":"Lin","year":"2022","journal-title":"J Biol Chem"},{"key":"2025090405302592500_ref47","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2022.5185","article-title":"ZNF667 facilitates angiogenesis after myocardial ischemia through transcriptional regulation of VASH1 and Wnt signaling pathway","volume":"50","author":"Wang","year":"2022","journal-title":"Int J Mol Med"},{"key":"2025090405302592500_ref48","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1073\/pnas.0908423107","article-title":"FRMD4A regulates epithelial polarity by connecting Arf6 activation with the PAR complex","volume":"107","author":"Ikenouchi","year":"2010","journal-title":"Proc Natl Acad Sci"},{"key":"2025090405302592500_ref49","doi-asserted-by":"publisher","first-page":"1097403","DOI":"10.3389\/fimmu.2023.1097403","article-title":"NCAPG2 could be an immunological and prognostic biomarker: from pan-cancer analysis to pancreatic cancer validation","volume":"14","author":"Wang","year":"2023","journal-title":"Front Immunol"},{"key":"2025090405302592500_ref50","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s12943-021-01316-8","article-title":"The cancer metabolic reprogramming and immune response","volume":"20","author":"Xia","year":"2021","journal-title":"Mol Cancer"},{"key":"2025090405302592500_ref51","doi-asserted-by":"publisher","first-page":"4","DOI":"10.4103\/jcar.JCar_15_20","article-title":"Lipid metabolism in cancer: a systematic review","volume":"20","author":"Khan","year":"2021","journal-title":"Journal of carcinogenesis"},{"key":"2025090405302592500_ref52","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1016\/j.cell.2015.08.016","article-title":"Metabolic competition in the tumor microenvironment is a driver of cancer progression","volume":"162","author":"Chang","year":"2015","journal-title":"Cell."}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf452\/64205797\/bbaf452.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/26\/5\/bbaf452\/64205797\/bbaf452.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T09:30:33Z","timestamp":1756978233000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbaf452\/8247776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,31]]},"references-count":52,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,8,31]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbaf452","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"type":"print","value":"1467-5463"},{"type":"electronic","value":"1477-4054"}],"subject":[],"published-other":{"date-parts":[[2025,9]]},"published":{"date-parts":[[2025,8,31]]},"article-number":"bbaf452"}}