{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T11:14:59Z","timestamp":1782126899741,"version":"3.54.5"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T00:00:00Z","timestamp":1664755200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T00:00:00Z","timestamp":1664755200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human cancers display a restricted set of expression profiles, despite diverse mutational drivers. This has led to the hypothesis that select sets of transcription factors act on similar target genes as an integrated network, buffering a tumor\u2019s transcriptional state. Noninvasive papillary urothelial carcinoma (NIPUC) with higher cell cycle activity has higher risk of recurrence and progression. In this paper, we describe a transcriptional network of cell cycle dysregulation in NIPUC, which was delineated using the ARACNe algorithm applied to expression data from a new cohort (n\u2009=\u200981, RNA sequencing), and two previously published cohorts. The transcriptional network comprised 121 transcription factors, including the pluripotency factors SOX2 and SALL4, the sex hormone binding receptors ESR1 and PGR, and multiple homeobox factors. Of these 121 transcription factors, 65 and 56 were more active in tumors with greater and less cell cycle activity, respectively. When clustered by activity of these transcription factors, tumors divided into High Cell Cycle versus Low Cell Cycle groups. Tumors in the High Cell Cycle group demonstrated greater mutational burden and copy number instability. A putative mutational driver of cell cycle dysregulation, such as homozygous loss of <jats:italic>CDKN2A<\/jats:italic>, was found in only 50% of High Cell Cycle NIPUC, suggesting a prominent role of transcription factor activity in driving cell cycle dysregulation. Activity of the 121 transcription factors strongly associated with expression of EZH2 and other members of the PRC2 complex, suggesting regulation by this complex influences expression of the transcription factors in this network. Activity of transcription factors in this network also associated with signatures of pluripotency and epithelial-to-mesenchymal transition (EMT), suggesting they play a role in driving evolution to invasive carcinoma. Consistent with this, these transcription factors differed in activity between NIPUC and invasive urothelial carcinoma.<\/jats:p>","DOI":"10.1038\/s41598-022-20927-9","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T16:05:26Z","timestamp":1664813126000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma"],"prefix":"10.1038","volume":"12","author":[{"given":"Joshua I.","family":"Warrick","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret A.","family":"Knowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn D.","family":"Hurst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Shuman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay D.","family":"Raman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vonn","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Putt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Dyrskj\u00f8t","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarice","family":"Groeneveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro A. A.","family":"Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Gordon","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"DeGraff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,3]]},"reference":[{"key":"20927_CR1","unstructured":"IARC. GLOBOCAN 2012 v1.0. Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. (2012). http:\/\/globocan.iarc.fr."},{"key":"20927_CR2","volume-title":"WHO Classification of Tumours of the Urinary System and Male Genital Organs","author":"H Moch","year":"2016","unstructured":"Moch, H., Cubilla, A. L., Humphrey, P. A., Reuter, V. E. & Ulbright, T. M. WHO Classification of Tumours of the Urinary System and Male Genital Organs (IARC, 2016)."},{"key":"20927_CR3","doi-asserted-by":"publisher","first-page":"2158","DOI":"10.1016\/j.juro.2011.07.076","volume":"186","author":"M Brausi","year":"2011","unstructured":"Brausi, M. et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J. Urol. 186, 2158\u20132167 (2011).","journal-title":"J. Urol."},{"key":"20927_CR4","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.humpath.2018.10.008","volume":"84","author":"M Zaleski","year":"2019","unstructured":"Zaleski, M. et al. Mitotic activity in noninvasive papillary urothelial carcinoma: Its value in predicting tumor recurrence and comparison with the contemporary 2-tier grading system. Hum. Pathol. 84, 275\u2013282 (2019).","journal-title":"Hum. Pathol."},{"key":"20927_CR5","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1097\/MD.0000000000000119","volume":"93","author":"MA Perez-Jacoiste Asin","year":"2014","unstructured":"Perez-Jacoiste Asin, M. A. et al. Bacillus Calmette-Guerin (BCG) infection following intravesical BCG administration as adjunctive therapy for bladder cancer: Incidence, risk factors, and outcome in a single-institution series and review of the literature. Medicine 93, 236\u2013254 (2014).","journal-title":"Medicine"},{"key":"20927_CR6","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1111\/j.1464-410X.2008.07743.x","volume":"102","author":"JP Stein","year":"2008","unstructured":"Stein, J. P. & Penson, D. F. Invasive T1 bladder cancer: Indications and rationale for radical cystectomy. BJU Int. 102, 270\u2013275 (2008).","journal-title":"BJU Int."},{"key":"20927_CR7","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/j.cell.2014.06.049","volume":"158","author":"KA Hoadley","year":"2014","unstructured":"Hoadley, K. A. et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158, 929\u2013944 (2014).","journal-title":"Cell"},{"key":"20927_CR8","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","volume":"173","author":"KA Hoadley","year":"2018","unstructured":"Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173, 291\u2013304 (2018).","journal-title":"Cell"},{"key":"20927_CR9","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/nrc.2016.124","volume":"17","author":"A Califano","year":"2017","unstructured":"Califano, A. & Alvarez, M. J. The recurrent architecture of tumour initiation, progression and drug sensitivity. Nat. Rev. Cancer. 17, 116\u2013130 (2017).","journal-title":"Nat. Rev. Cancer."},{"key":"20927_CR10","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1097\/PAS.0000000000001453","volume":"44","author":"JI Warrick","year":"2020","unstructured":"Warrick, J. I. et al. Report from the international society of urological pathology (ISUP) consultation conference on molecular pathology of urogenital cancers. II. Molecular pathology of bladder cancer: progress and challenges. Am. J. Surg. Pathol. 44, 30\u201346 (2020).","journal-title":"Am. J. Surg. Pathol."},{"key":"20927_CR11","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.ccell.2016.05.004","volume":"30","author":"J Hedegaard","year":"2016","unstructured":"Hedegaard, J. et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30, 27\u201342 (2016).","journal-title":"Cancer Cell"},{"key":"20927_CR12","doi-asserted-by":"publisher","first-page":"2301","DOI":"10.1038\/s41467-021-22465-w","volume":"12","author":"SV Lindskrog","year":"2021","unstructured":"Lindskrog, S. V. et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat. Commun. 12, 2301 (2021).","journal-title":"Nat. Commun."},{"key":"20927_CR13","doi-asserted-by":"crossref","unstructured":"Hurst C, et al. Cell Rep Med. 2021 Dec 21;2(12):100472.","DOI":"10.1016\/j.xcrm.2021.100472"},{"issue":"540\u2013556","key":"20927_CR14","volume":"171","author":"AG Robertson","year":"2017","unstructured":"Robertson, A. G. et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171(540\u2013556), e525 (2017).","journal-title":"Cell"},{"key":"20927_CR15","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/ng.3458","volume":"48","author":"MA Castro","year":"2016","unstructured":"Castro, M. A. et al. Regulators of genetic risk of breast cancer identified by integrative network analysis. Nat. Genet. 48, 12\u201321 (2016).","journal-title":"Nat. Genet."},{"key":"20927_CR16","doi-asserted-by":"publisher","first-page":"2464","DOI":"10.1038\/ncomms3464","volume":"4","author":"MN Fletcher","year":"2013","unstructured":"Fletcher, M. N. et al. Master regulators of FGFR2 signalling and breast cancer risk. Nat. Commun. 4, 2464 (2013).","journal-title":"Nat. Commun."},{"issue":"Suppl 1","key":"20927_CR17","doi-asserted-by":"publisher","first-page":"S7","DOI":"10.1186\/1471-2105-7-S1-S7","volume":"7","author":"AA Margolin","year":"2006","unstructured":"Margolin, A. A. et al. ARACNE: An algorithm for the reconstruction of gene regulatory networks in a mammalian cellular context. BMC Bioinform. 7(Suppl 1), S7 (2006).","journal-title":"BMC Bioinform."},{"key":"20927_CR18","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.cell.2018.09.045","volume":"175","author":"SA Lambert","year":"2018","unstructured":"Lambert, S. A. et al. The human transcription factors. Cell 175, 598\u2013599 (2018).","journal-title":"Cell"},{"key":"20927_CR19","doi-asserted-by":"publisher","first-page":"38531","DOI":"10.1038\/srep38531","volume":"6","author":"JI Warrick","year":"2016","unstructured":"Warrick, J. I. et al. FOXA1, GATA3 and PPAR cooperate to drive luminal subtype in bladder cancer: A molecular analysis of established human cell lines. Sci. Rep. 6, 38531 (2016).","journal-title":"Sci. Rep."},{"key":"20927_CR20","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/ng.127","volume":"40","author":"I Ben-Porath","year":"2008","unstructured":"Ben-Porath, I. et al. An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat. Genet. 40, 499\u2013507 (2008).","journal-title":"Nat. Genet."},{"key":"20927_CR21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051136","volume":"7","author":"CJ Groger","year":"2012","unstructured":"Groger, C. J. et al. Meta-analysis of gene expression signatures defining the epithelial to mesenchymal transition during cancer progression. PLoS ONE 7, e51136 (2012).","journal-title":"PLoS ONE"},{"key":"20927_CR22","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/s41580-020-0237-9","volume":"21","author":"J Yang","year":"2020","unstructured":"Yang, J. et al. Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell. Biol. 21, 341\u2013352 (2020).","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"20927_CR23","doi-asserted-by":"publisher","first-page":"e251","DOI":"10.1016\/j.urolonc.2016.02.011","volume":"34","author":"JI Warrick","year":"2016","unstructured":"Warrick, J. I. et al. Enhancer of zeste homolog 2 (EZH2) expression in bladder cancer. Urol. Oncol. 34, e251-256 (2016).","journal-title":"Urol. Oncol."},{"key":"20927_CR24","doi-asserted-by":"publisher","first-page":"4488","DOI":"10.1093\/bioinformatics\/btz229","volume":"35","author":"CS Groeneveld","year":"2019","unstructured":"Groeneveld, C. S. et al. RTNsurvival: An R\/Bioconductor package for regulatory network survival analysis. Bioinformatics 35, 4488\u20134489 (2019).","journal-title":"Bioinformatics"},{"key":"20927_CR25","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1016\/j.eururo.2017.05.032","volume":"72","author":"EJ Pietzak","year":"2017","unstructured":"Pietzak, E. J. et al. Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets. Eur. Urol. 72, 952\u2013959 (2017).","journal-title":"Eur. Urol."},{"key":"20927_CR26","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.ccell.2017.08.005","volume":"32","author":"CD Hurst","year":"2017","unstructured":"Hurst, C. D. et al. Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell 32, 701\u2013715 (2017).","journal-title":"Cancer Cell"},{"key":"20927_CR27","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/path.4017","volume":"227","author":"S Rebouissou","year":"2012","unstructured":"Rebouissou, S. et al. CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. J. Pathol. 227, 315\u2013324 (2012).","journal-title":"J. Pathol."},{"key":"20927_CR28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036530","volume":"7","author":"MD Wilkerson","year":"2012","unstructured":"Wilkerson, M. D. et al. Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. PLoS ONE 7, e36530 (2012).","journal-title":"PLoS ONE"},{"key":"20927_CR29","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1186\/1471-2105-12-480","volume":"12","author":"D Risso","year":"2011","unstructured":"Risso, D. et al. GC-content normalization for RNA-Seq data. BMC Bioinform. 12, 480 (2011).","journal-title":"BMC Bioinform."},{"key":"20927_CR30","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/nbt.2931","volume":"32","author":"D Risso","year":"2014","unstructured":"Risso, D. et al. Normalization of RNA-seq data using factor analysis of control genes or samples. Nat. Biotechnol. 32, 896\u2013902 (2014).","journal-title":"Nat. Biotechnol."},{"key":"20927_CR31","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1002\/dvdy.24678","volume":"248","author":"H Wang","year":"2019","unstructured":"Wang, H. & Unternaehrer, J. J. Epithelial-mesenchymal transition and cancer stem cells: at the crossroads of differentiation and dedifferentiation. Dev. Dyn. 248, 10\u201320 (2019).","journal-title":"Dev. Dyn."},{"key":"20927_CR32","volume-title":"The Biology of Cancer","author":"RA Weinberg","year":"2014","unstructured":"Weinberg, R. A. The Biology of Cancer (Garland Science, Taylor & Francis Group, 2014)."},{"key":"20927_CR33","doi-asserted-by":"publisher","first-page":"2979","DOI":"10.1093\/hmg\/11.23.2979","volume":"11","author":"J Kohlhase","year":"2002","unstructured":"Kohlhase, J. et al. Okihiro syndrome is caused by SALL4 mutations. Hum. Mol. Genet. 11, 2979\u20132987 (2002).","journal-title":"Hum. Mol. Genet."},{"key":"20927_CR34","doi-asserted-by":"publisher","first-page":"20584","DOI":"10.1073\/pnas.1208651109","volume":"109","author":"Y Fujii","year":"2012","unstructured":"Fujii, Y. et al. CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5. Proc. Natl. Acad. Sci. USA 109, 20584\u201320589 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"20927_CR35","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.stem.2011.09.001","volume":"9","author":"K Arnold","year":"2011","unstructured":"Arnold, K. et al. Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 9, 317\u2013329 (2011).","journal-title":"Cell Stem Cell"},{"key":"20927_CR36","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.gene.2016.02.019","volume":"584","author":"H Tatetsu","year":"2016","unstructured":"Tatetsu, H. et al. SALL4, the missing link between stem cells, development and cancer. Gene 584, 111\u2013119 (2016).","journal-title":"Gene"},{"key":"20927_CR37","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","volume":"126","author":"K Takahashi","year":"2006","unstructured":"Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663\u2013676 (2006).","journal-title":"Cell"},{"key":"20927_CR38","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","volume":"131","author":"K Takahashi","year":"2007","unstructured":"Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861\u2013872 (2007).","journal-title":"Cell"},{"key":"20927_CR39","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1038\/s41388-019-0997-x","volume":"39","author":"T Schaefer","year":"2020","unstructured":"Schaefer, T. & Lengerke, C. SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K\/AKT\/SOX2 axis and beyond. Oncogene 39, 278\u2013292 (2020).","journal-title":"Oncogene"},{"key":"20927_CR40","doi-asserted-by":"publisher","first-page":"4459","DOI":"10.2147\/CMAR.S177373","volume":"10","author":"X Zhang","year":"2018","unstructured":"Zhang, X. et al. SALL4 activates TGF-beta\/SMAD signaling pathway to induce EMT and promote gastric cancer metastasis. Cancer Manag. Res. 10, 4459\u20134470 (2018).","journal-title":"Cancer Manag. Res."},{"key":"20927_CR41","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.stemcr.2017.07.004","volume":"9","author":"F Zhu","year":"2017","unstructured":"Zhu, F. et al. SOX2 is a marker for stem-like tumor cells in bladder cancer. Stem Cell Rep. 9, 429\u2013437 (2017).","journal-title":"Stem Cell Rep."},{"key":"20927_CR42","first-page":"E7119","volume":"115","author":"BH Liu","year":"2018","unstructured":"Liu, B. H. et al. Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide. Proc. Natl. Acad. Sci. USA. 115, E7119\u2013E7128 (2018).","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"20927_CR43","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1073\/pnas.7.4.127","volume":"7","author":"CB Bridges","year":"1921","unstructured":"Bridges, C. B. Current maps of the location of the mutant genes of drosophila melanogaster. Proc. Natl. Acad. Sci. USA 7, 127\u2013132 (1921).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"20927_CR44","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/0092-8674(85)90007-8","volume":"43","author":"CP Hart","year":"1985","unstructured":"Hart, C. P. et al. Homeo box gene complex on mouse chromosome 11: Molecular cloning, expression in embryogenesis, and homology to a human homeo box locus. Cell 43, 9\u201318 (1985).","journal-title":"Cell"},{"key":"20927_CR45","first-page":"L429","volume":"269","author":"WV Cardoso","year":"1995","unstructured":"Cardoso, W. V. Transcription factors and pattern formation in the developing lung. Am. J. Physiol. 269, L429-442 (1995).","journal-title":"Am. J. Physiol."},{"key":"20927_CR46","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1002\/(SICI)1096-8628(19991229)89:4<224::AID-AJMG7>3.0.CO;2-C","volume":"89","author":"JL Simpson","year":"1999","unstructured":"Simpson, J. L. Genetics of the female reproductive ducts. Am. J. Med. Genet. 89, 224\u2013239 (1999).","journal-title":"Am. J. Med. Genet."},{"key":"20927_CR47","doi-asserted-by":"publisher","first-page":"3967","DOI":"10.1242\/dev.010991","volume":"134","author":"G Zacchetti","year":"2007","unstructured":"Zacchetti, G., Duboule, D. & Zakany, J. Hox gene function in vertebrate gut morphogenesis: the case of the caecum. Development 134, 3967\u20133973 (2007).","journal-title":"Development"},{"key":"20927_CR48","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nrc2826","volume":"10","author":"N Shah","year":"2010","unstructured":"Shah, N. & Sukumar, S. The Hox genes and their roles in oncogenesis. Nat. Rev. Cancer. 10, 361\u2013371 (2010).","journal-title":"Nat. Rev. Cancer."},{"key":"20927_CR49","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1002\/pros.20443","volume":"66","author":"T Kikugawa","year":"2006","unstructured":"Kikugawa, T. et al. PLZF regulates Pbx1 transcription and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer proliferation. Prostate 66, 1092\u20131099 (2006).","journal-title":"Prostate"},{"key":"20927_CR50","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1002\/pros.10045","volume":"50","author":"D Waltregny","year":"2002","unstructured":"Waltregny, D. et al. Overexpression of the homeobox gene HOXC8 in human prostate cancer correlates with loss of tumor differentiation. Prostate 50, 162\u2013169 (2002).","journal-title":"Prostate"},{"key":"20927_CR51","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.1242\/dev.00432","volume":"130","author":"KD Economides","year":"2003","unstructured":"Economides, K. D. & Capecchi, M. R. Hoxb13 is required for normal differentiation and secretory function of the ventral prostate. Development 130, 2061\u20132069 (2003).","journal-title":"Development"},{"key":"20927_CR52","doi-asserted-by":"publisher","first-page":"3046","DOI":"10.1158\/0008-5472.CAN-03-2614","volume":"64","author":"C Jung","year":"2004","unstructured":"Jung, C. et al. HOXB13 homeodomain protein suppresses the growth of prostate cancer cells by the negative regulation of T-cell factor 4. Cancer Res. 64, 3046\u20133051 (2004).","journal-title":"Cancer Res."},{"key":"20927_CR53","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.ccr.2004.05.015","volume":"5","author":"XJ Ma","year":"2004","unstructured":"Ma, X. J. et al. A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 5, 607\u2013616 (2004).","journal-title":"Cancer Cell"},{"key":"20927_CR54","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1093\/annonc\/mdz289","volume":"30","author":"JMS Bartlett","year":"2019","unstructured":"Bartlett, J. M. S. et al. Breast cancer index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the adjuvant tamoxifen-to offer more? (aTTom) trial. Ann. Oncol. 30, 1776\u20131783 (2019).","journal-title":"Ann. Oncol."},{"key":"20927_CR55","doi-asserted-by":"publisher","first-page":"6462","DOI":"10.1038\/sj.onc.1206808","volume":"22","author":"M Cantile","year":"2003","unstructured":"Cantile, M. et al. Hyperexpression of locus C genes in the HOX network is strongly associated in vivo with human bladder transitional cell carcinomas. Oncogene 22, 6462\u20136468 (2003).","journal-title":"Oncogene"},{"key":"20927_CR56","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s13073-015-0144-4","volume":"7","author":"M Aine","year":"2015","unstructured":"Aine, M. et al. Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma. Genome Med. 7, 23 (2015).","journal-title":"Genome Med."},{"key":"20927_CR57","doi-asserted-by":"crossref","unstructured":"Marzouka N, et al. J Mol Diagn. 2022 Sep;24(9):992-1008","DOI":"10.1016\/j.jmoldx.2022.05.006"},{"key":"20927_CR58","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.urolonc.2019.01.023","volume":"37","author":"Y Imai","year":"2019","unstructured":"Imai, Y. et al. Sex steroid hormone receptors in bladder cancer: Usefulness in differential diagnosis and implications in histogenesis of bladder cancer. Urol. Oncol. 37, 353 (2019).","journal-title":"Urol. Oncol."},{"key":"20927_CR59","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.684140","volume":"12","author":"C Bernardo","year":"2021","unstructured":"Bernardo, C. et al. Association between estrogen receptors and GATA3 in bladder cancer: A systematic review and meta-analysis of their clinicopathological significance. Front. Endocrinol. 12, 684140 (2021).","journal-title":"Front. Endocrinol."},{"key":"20927_CR60","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1007\/s00428-016-2002-1","volume":"469","author":"J Breyer","year":"2016","unstructured":"Breyer, J. et al. ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle-invasive bladder carcinoma (NMIBC). Virchows Arch. 469, 547\u2013552 (2016).","journal-title":"Virchows Arch."},{"key":"20927_CR61","volume-title":"Gene Control","author":"DS Latchman","year":"2015","unstructured":"Latchman, D. S. Gene Control (Taylor & Francis Group, 2015)."},{"key":"20927_CR62","doi-asserted-by":"publisher","first-page":"5449","DOI":"10.1158\/0008-5472.CAN-20-2147","volume":"80","author":"ML Eich","year":"2020","unstructured":"Eich, M. L. et al. EZH2-targeted therapies in cancer: Hype or a reality. Cancer Res. 80, 5449\u20135458 (2020).","journal-title":"Cancer Res."},{"issue":"755\u2013770","key":"20927_CR63","volume":"30","author":"S Yomtoubian","year":"2020","unstructured":"Yomtoubian, S. et al. Inhibition of EZH2 catalytic activity selectively targets a metastatic subpopulation in triple-negative breast cancer. Cell Rep. 30(755\u2013770), e756 (2020).","journal-title":"Cell Rep."},{"key":"20927_CR64","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1016\/S1470-2045(20)30441-1","volume":"21","author":"F Morschhauser","year":"2020","unstructured":"Morschhauser, F. et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: An open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 21, 1433\u20131442 (2020).","journal-title":"Lancet Oncol."},{"key":"20927_CR65","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/S1470-2045(20)30451-4","volume":"21","author":"M Gounder","year":"2020","unstructured":"Gounder, M. et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1\/SMARCB1: An international, open-label, phase 2 basket study. Lancet Oncol. 21, 1423\u20131432 (2020).","journal-title":"Lancet Oncol."},{"key":"20927_CR66","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq: A Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169 (2015).","journal-title":"Bioinformatics"},{"key":"20927_CR67","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140 (2010).","journal-title":"Bioinformatics"},{"key":"20927_CR68","doi-asserted-by":"publisher","first-page":"1572","DOI":"10.1093\/bioinformatics\/btq170","volume":"26","author":"MD Wilkerson","year":"2010","unstructured":"Wilkerson, M. D. & Hayes, D. N. ConsensusClusterPlus: A class discovery tool with confidence assessments and item tracking. Bioinformatics 26, 1572\u20131573 (2010).","journal-title":"Bioinformatics"},{"key":"20927_CR69","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1023\/A:1023949509487","volume":"52","author":"S Monti","year":"2003","unstructured":"Monti, S. et al. Consensus clustering: A resampling-based method for class discovery and visualization of gene expression microarray data. Mach. Learn. 52, 91\u2013118 (2003).","journal-title":"Mach. Learn."},{"key":"20927_CR70","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545\u201315550 (2005).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"20927_CR71","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/ng1180","volume":"34","author":"VK Mootha","year":"2003","unstructured":"Mootha, V. K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267\u2013273 (2003).","journal-title":"Nat. Genet."},{"key":"20927_CR72","unstructured":"Institute B. GSEA Graphical Interface. https:\/\/www.gsea-msigdb.org\/gsea\/downloads.jsp."},{"key":"20927_CR73","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","volume":"14","author":"S Hanzelmann","year":"2013","unstructured":"Hanzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 14, 7 (2013).","journal-title":"BMC Bioinform."},{"key":"20927_CR74","doi-asserted-by":"publisher","first-page":"5357","DOI":"10.1093\/bioinformatics\/btz534","volume":"35","author":"VS Chagas","year":"2019","unstructured":"Chagas, V. S. et al. RTNduals: An R\/Bioconductor package for analysis of co-regulation and inference of dual regulons. Bioinformatics 35, 5357\u20135358 (2019).","journal-title":"Bioinformatics"},{"key":"20927_CR75","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1507","volume":"44","author":"A Colaprico","year":"2016","unstructured":"Colaprico, A. et al. TCGAbiolinks: An R\/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 44, e71 (2016).","journal-title":"Nucleic Acids Res."},{"key":"20927_CR76","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.12688\/f1000research.8923.1","volume":"5","author":"TC Silva","year":"2016","unstructured":"Silva, T. C. et al. TCGA Workflow: Analyze cancer genomics and epigenomics data using Bioconductor packages. F1000 Res. 5, 1542 (2016).","journal-title":"F1000 Res."},{"key":"20927_CR77","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006701","volume":"15","author":"M Mounir","year":"2019","unstructured":"Mounir, M. et al. New functionalities in the TCGAbiolinks package for the study and integration of cancer data from GDC and GTEx. PLoS Comput. Biol. 15, e1006701 (2019).","journal-title":"PLoS Comput. Biol."},{"key":"20927_CR78","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/j.tig.2013.05.010","volume":"29","author":"E Eisenberg","year":"2013","unstructured":"Eisenberg, E. & Levanon, E. Y. Human housekeeping genes, revisited. Trends Genet. 29, 569\u2013574 (2013).","journal-title":"Trends Genet."},{"key":"20927_CR79","unstructured":"Kuliman, T. CopywriteR: Copy number information from targeted sequencing using off-target reads. R Package Version 2.24.0. (2021). https:\/\/github.com\/PeeperLab\/CopywriteR."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-20927-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-20927-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-20927-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T16:24:15Z","timestamp":1664814255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-20927-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,3]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["20927"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-20927-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,3]]},"assertion":[{"value":"14 April 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 September 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 October 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"MK\u2014advisory\/consulting role at Janssen, QED, Loxo Oncology and Rainier Therapeutics; DJD\u2014grant support from GlaxoSmithKlein, separate from this project; the other authors do not have competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16538"}}