{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T08:56:32Z","timestamp":1789721792436,"version":"4.0.1"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T00:00:00Z","timestamp":1662508800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T00:00:00Z","timestamp":1662508800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["332697"],"award-info":[{"award-number":["332697"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Sy\u00f6p\u00e4s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007083","name":"Orionin Tutkimuss\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007083","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003756","name":"Biomedicum Helsinki-s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003756","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007753","name":"It\u00e4-Suomen Yliopisto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007753","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Oncogenesis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Uterine leiomyomas, or fibroids, are the most common tumors in women of reproductive age. Uterine leiomyomas can be classified into at least three main molecular subtypes according to mutations affecting <jats:italic>MED12<\/jats:italic>, <jats:italic>HMGA2<\/jats:italic>, or <jats:italic>FH<\/jats:italic>. FH-deficient leiomyomas are characterized by activation of the NRF2 pathway, including upregulation of the NRF2 target gene <jats:italic>AKR1B10<\/jats:italic>. Here, we have identified a novel leiomyoma subtype showing AKR1B10 expression but no alterations in <jats:italic>FH<\/jats:italic> or other known driver genes. Whole-exome and whole-genome sequencing revealed biallelic mutations in key genes involved in neddylation of the Cullin 3-RING E3 ligase, including <jats:italic>UBE2M<\/jats:italic>, <jats:italic>NEDD8<\/jats:italic>, <jats:italic>CUL3<\/jats:italic>, and <jats:italic>NAE1<\/jats:italic>. 3\u2032RNA sequencing confirmed a distinct molecular subtype with activation of the NRF2 pathway. Most tumors displayed cellular histopathology, perivascular hypercellularity, and characteristics typically seen in FH-deficient leiomyomas. These results suggest a novel leiomyoma subtype that is characterized by distinct morphological features, genetic alterations disrupting neddylation of the Cullin 3-RING E3 ligase, and oncogenic NRF2 activation. They also present defective neddylation as a novel mechanism leading to aberrant NRF2 signaling. Molecular characterization of uterine leiomyomas provides novel opportunities for targeted treatment options.<\/jats:p>","DOI":"10.1038\/s41389-022-00425-3","type":"journal-article","created":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T03:19:39Z","timestamp":1662520779000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["A novel uterine leiomyoma subtype exhibits NRF2 activation and mutations in genes associated with neddylation of the Cullin 3-RING E3 ligase"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0443-0625","authenticated-orcid":false,"given":"Miika","family":"Mehine","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terhi","family":"Ahvenainen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Khamaiseh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouni","family":"H\u00e4rk\u00f6nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3812-4418","authenticated-orcid":false,"given":"Siiri","family":"Reinikka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomas","family":"Heikkinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"\u00c4yr\u00e4v\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"Pakarinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"H\u00e4rkki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annukka","family":"Pasanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Liisa","family":"Levonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"B\u00fctzow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4615-3825","authenticated-orcid":false,"given":"Pia","family":"Vahteristo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,9,7]]},"reference":[{"key":"425_CR1","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1056\/NEJMcp1411029","volume":"372","author":"EA Stewart","year":"2015","unstructured":"Stewart EA. Clinical practice. Uterine fibroids. N Engl J Med. 2015;372:1646\u201355.","journal-title":"N Engl J Med."},{"key":"425_CR2","doi-asserted-by":"publisher","first-page":"211.e211","DOI":"10.1016\/j.ajog.2011.12.002","volume":"206","author":"ER Cardozo","year":"2012","unstructured":"Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012;206:211.e211\u20139.","journal-title":"Am J Obstet Gynecol"},{"key":"425_CR3","unstructured":"Ip PPC, Bennett JA, Croce S, Garg K, Yang B. Uterine leiomyoma. In: Rabban JT, Nucci MR, Malpica A, Brenton JD, Hui P, Ordi J et al., editors. WHO classification of tumors: female genital tumours. 5th edn. Lyon, France: IARC Publications; 2020. pp 272\u20136."},{"key":"425_CR4","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.fertnstert.2014.06.050","volume":"102","author":"M Mehine","year":"2014","unstructured":"Mehine M, M\u00e4kinen N, Heinonen HR, Aaltonen LA, Vahteristo P. Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertil Steril. 2014;102:621\u20139.","journal-title":"Fertil Steril."},{"key":"425_CR5","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1038\/ng849","volume":"30","author":"IP Tomlinson","year":"2002","unstructured":"Tomlinson IP, Alam NA, Rowan AJ, Barclay E, Jaeger EE, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406\u201310.","journal-title":"Nat Genet."},{"key":"425_CR6","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/s41586-021-03747-1","volume":"596","author":"DG Berta","year":"2021","unstructured":"Berta DG, Kuisma H, V\u00e4lim\u00e4ki N, R\u00e4is\u00e4nen M, J\u00e4ntti M, Pasanen A, et al. Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma. Nature. 2021;596:398\u2013403.","journal-title":"Nature."},{"key":"425_CR7","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-017-0672-1","volume":"16","author":"N M\u00e4kinen","year":"2017","unstructured":"M\u00e4kinen N, K\u00e4mpj\u00e4rvi K, Frizzell N, B\u00fctzow R, Vahteristo P. Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. Mol Cancer. 2017;16:101.","journal-title":"Mol Cancer."},{"key":"425_CR8","doi-asserted-by":"publisher","first-page":"572 e571","DOI":"10.1016\/j.ajog.2014.01.011","volume":"210","author":"JC Hodge","year":"2014","unstructured":"Hodge JC, Pearce KE, Clayton AC, Taran FA, Stewart EA. Uterine cellular leiomyomata with chromosome 1p deletions represent a distinct entity. Am J Obstet Gynecol. 2014;210:572 e571\u201377.","journal-title":"Am J Obstet Gynecol."},{"key":"425_CR9","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1073\/pnas.1518752113","volume":"113","author":"M Mehine","year":"2016","unstructured":"Mehine M, Kaasinen E, Heinonen HR, Makinen N, Kampjarvi K, Sarvilinna N, et al. Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proc Natl Acad Sci USA. 2016;113:1315\u201320.","journal-title":"Proc Natl Acad Sci USA"},{"key":"425_CR10","doi-asserted-by":"publisher","first-page":"143","DOI":"10.3390\/biom10010143","volume":"10","author":"P Podkalicka","year":"2020","unstructured":"Podkalicka P, Mucha O, Kruczek S, Biela A, Andrysiak K, St\u0119pniewski J, et al. Synthetically lethal interactions of heme oxygenase-1 and fumarate hydratase genes. Biomolecules. 2020;10:143.","journal-title":"Biomolecules."},{"key":"425_CR11","doi-asserted-by":"publisher","first-page":"4376","DOI":"10.3390\/ijms22094376","volume":"22","author":"MY Song","year":"2021","unstructured":"Song MY, Lee DY, Chun KS, Kim EH. The role of NRF2\/KEAP1 signaling pathway in cancer metabolism. Int J Mol Sci. 2021;22:4376.","journal-title":"Int J Mol Sci."},{"key":"425_CR12","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1016\/j.ccr.2011.08.024","volume":"20","author":"A Ooi","year":"2011","unstructured":"Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell. 2011;20:511\u201323.","journal-title":"Cancer Cell."},{"key":"425_CR13","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1126\/science.aax3769","volume":"366","author":"C Pohl","year":"2019","unstructured":"Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019;366:818\u201322.","journal-title":"Science."},{"key":"425_CR14","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.ccell.2018.03.022","volume":"34","author":"M Rojo de la Vega","year":"2018","unstructured":"Rojo de la Vega M, Chapman E, Zhang DD. NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018;34:21\u201343.","journal-title":"Cancer Cell."},{"key":"425_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-31281-0","volume":"8","author":"MJ Kerins","year":"2018","unstructured":"Kerins MJ, Ooi A. A catalogue of somatic NRF2 gain-of-function mutations in cancer. Sci Rep. 2018;8:12846.","journal-title":"Sci Rep."},{"key":"425_CR16","doi-asserted-by":"publisher","first-page":"3839","DOI":"10.3390\/cancers12123839","volume":"12","author":"M Mehine","year":"2020","unstructured":"Mehine M, Khamaiseh S, Ahvenainen T, Heikkinen T, Ayravainen A, Pakarinen P, et al. 3\u2032RNA sequencing accurately classifies formalin-fixed paraffin-embedded uterine leiomyomas. Cancers (Basel). 2020;12:3839.","journal-title":"Cancers (Basel)."},{"key":"425_CR17","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1097\/PAS.0000000000001826","volume":"46","author":"T Ahvenainen","year":"2022","unstructured":"Ahvenainen T, Kaukomaa J, K\u00e4mpj\u00e4rvi K, Uimari O, Ahtikoski A, M\u00e4kinen N, et al. Comparison of 2SC, AKR1B10, and FH antibodies as potential biomarkers for FH-deficient uterine leiomyomas. Am J Surg Pathol. 2022;46:537\u201346.","journal-title":"Am J Surg Pathol"},{"key":"425_CR18","doi-asserted-by":"publisher","first-page":"1300","DOI":"10.1038\/ejhg.2013.33","volume":"21","author":"N M\u00e4kinen","year":"2013","unstructured":"M\u00e4kinen N, Vahteristo P, K\u00e4mpj\u00e4rvi K, Arola J, B\u00fctzow R, Aaltonen LA. MED12 exon 2 mutations in histopathological uterine leiomyoma variants. Eur J Hum Genet. 2013;21:1300\u201303.","journal-title":"Eur J Hum Genet."},{"key":"425_CR19","doi-asserted-by":"publisher","first-page":"4650","DOI":"10.1002\/cncr.31754","volume":"124","author":"TV Ahvenainen","year":"2018","unstructured":"Ahvenainen TV, M\u00e4kinen NM, von Nandelstadh P, Vahteristo MEA, Pasanen AM, B\u00fctzow RC, et al. Loss of ATRX\/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas. Cancer. 2018;124:4650\u201356.","journal-title":"Cancer."},{"key":"425_CR20","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1093\/humrep\/deaa187","volume":"35","author":"A \u00c4yr\u00e4v\u00e4inen","year":"2020","unstructured":"\u00c4yr\u00e4v\u00e4inen A, Pasanen A, Ahvenainen T, Heikkinen T, Pakarinen P, H\u00e4rkki P, et al. Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy. Hum Reprod. 2020;35:2237\u201344.","journal-title":"Hum Reprod."},{"key":"425_CR21","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","volume":"35","author":"C Kopanos","year":"2019","unstructured":"Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, Meyer R, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978\u201380.","journal-title":"Bioinformatics."},{"key":"425_CR22","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","volume":"47","author":"P Rentzsch","year":"2019","unstructured":"Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886\u201394.","journal-title":"Nucleic Acids Res."},{"key":"425_CR23","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.bbcan.2017.11.001","volume":"1869","author":"J Cheng","year":"2018","unstructured":"Cheng J, Guo J, Wang Z, North BJ, Tao K, Dai X, et al. Functional analysis of Cullin 3 E3 ligases in tumorigenesis. Biochim Biophys Acta Rev Cancer. 2018;1869:11\u201328.","journal-title":"Biochim Biophys Acta Rev Cancer."},{"key":"425_CR24","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1016\/j.molcel.2018.06.002","volume":"70","author":"W Zhou","year":"2018","unstructured":"Zhou W, Xu J, Tan M, Li H, Li H, Wei W, et al. UBE2M is a stress-inducible dual E2 for neddylation and ubiquitylation that promotes targeted degradation of UBE2F. Mol Cell. 2018;70:1008\u20131024. e1006.","journal-title":"Mol Cell."},{"key":"425_CR25","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nrm3919","volume":"16","author":"RI Enchev","year":"2015","unstructured":"Enchev RI, Schulman BA, Peter M. Protein neddylation: beyond cullin-RING ligases. Nat Rev Mol Cell Biol. 2015;16:30\u201344.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"425_CR26","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.sbi.2020.10.007","volume":"67","author":"K Baek","year":"2020","unstructured":"Baek K, Scott DC, Schulman BA. NEDD8 and ubiquitin ligation by cullin-RING E3 ligases. Curr Opin Struct Biol. 2020;67:101\u20139.","journal-title":"Curr Opin Struct Biol."},{"key":"425_CR27","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1128\/MCB.26.4.1235-1244.2006","volume":"26","author":"SC Lo","year":"2006","unstructured":"Lo SC, Hannink M. CAND1-mediated substrate adaptor recycling is required for efficient repression of Nrf2 by Keap1. Mol Cell Biol. 2006;26:1235\u201344.","journal-title":"Mol Cell Biol."},{"key":"425_CR28","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1091\/mbc.e06-06-0542","volume":"18","author":"W Wimuttisuk","year":"2007","unstructured":"Wimuttisuk W, Singer JD. The Cullin3 ubiquitin ligase functions as a Nedd8-bound heterodimer. Mol Biol Cell. 2007;18:899\u2013909.","journal-title":"Mol Biol Cell."},{"key":"425_CR29","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/nature07884","volume":"458","author":"TA Soucy","year":"2009","unstructured":"Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009;458:732\u20136.","journal-title":"Nature."},{"key":"425_CR30","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.redox.2016.02.008","volume":"8","author":"AC And\u00e9rica-Romero","year":"2016","unstructured":"And\u00e9rica-Romero AC, Hern\u00e1ndez-Dami\u00e1n J, V\u00e1zquez-Cervantes GI, Torres I, Gonz\u00e1lez-Herrera IG, Pedraza-Chaverri J. The MLN4924 inhibitor exerts a neuroprotective effect against oxidative stress injury via Nrf2 protein accumulation. Redox Biol. 2016;8:341\u20137.","journal-title":"Redox Biol."},{"key":"425_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01243-7","volume":"8","author":"H Zhou","year":"2017","unstructured":"Zhou H, Lu J, Liu L, Bernard D, Yang CY, Fernandez-Salas E, et al. A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation. Nat Commun. 2017;8:1150.","journal-title":"Nat Commun."},{"key":"425_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22924-4","volume":"12","author":"H Zhou","year":"2021","unstructured":"Zhou H, Lu J, Chinnaswamy K, Stuckey JA, Liu L, McEachern D, et al. Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity. Nat Commun. 2021;12:2621.","journal-title":"Nat Commun."},{"key":"425_CR33","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.1038\/sj.onc.1205390","volume":"21","author":"OL Caballero","year":"2002","unstructured":"Caballero OL, Resto V, Patturajan M, Meerzaman D, Guo MZ, Engles J, et al. Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1). Oncogene. 2002;21:3003\u201310.","journal-title":"Oncogene."},{"key":"425_CR34","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.3390\/biom10071082","volume":"10","author":"W Dubiel","year":"2020","unstructured":"Dubiel W, Chaithongyot S, Dubiel D, Naumann M. The COP9 Signalosome: a multi-DUB complex. Biomolecules. 2020;10:1082.","journal-title":"Biomolecules."},{"key":"425_CR35","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1006\/bbrc.1998.9532","volume":"251","author":"H Wada","year":"1998","unstructured":"Wada H, Kito K, Caskey LS, Yeh ET, Kamitani T. Cleavage of the C-terminus of NEDD8 by UCH-L3. Biochem Biophys Res Commun. 1998;251:688\u201392.","journal-title":"Biochem Biophys Res Commun."},{"key":"425_CR36","doi-asserted-by":"publisher","first-page":"2453","DOI":"10.1042\/BCJ20160082","volume":"473","author":"P Bishop","year":"2016","unstructured":"Bishop P, Rocca D, Henley JM. Ubiquitin C-terminal hydrolase L1 (UCH-L1): structure, distribution and roles in brain function and dysfunction. Biochem J. 2016;473:2453\u201362.","journal-title":"Biochem J."},{"key":"425_CR37","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1097\/PAS.0000000000000703","volume":"40","author":"M Miettinen","year":"2016","unstructured":"Miettinen M, Felisiak-Golabek A, Wasag B, Chmara M, Wang Z, Butzow R, et al. Fumarase-deficient uterine leiomyomas: an immunohistochemical, molecular genetic, and clinicopathologic study of 86 cases. Am J Surg Pathol. 2016;40:1661\u20139.","journal-title":"Am J Surg Pathol."},{"key":"425_CR38","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1097\/PAS.0b013e31825ec16f","volume":"37","author":"J Sanz-Ortega","year":"2013","unstructured":"Sanz-Ortega J, Vocke C, Stratton P, Linehan WM, Merino MJ. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 2013;37:74\u201380.","journal-title":"Am J Surg Pathol."},{"key":"425_CR39","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1002\/gcc.20291","volume":"45","author":"NC Christacos","year":"2006","unstructured":"Christacos NC, Quade BJ, Dal Cin P, Morton CC. Uterine leiomyomata with deletions of Ip represent a distinct cytogenetic subgroup associated with unusual histologic features. Genes Chromosomes Cancer. 2006;45:304\u201312.","journal-title":"Genes Chromosomes Cancer."},{"key":"425_CR40","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1002\/gcc.20018","volume":"40","author":"BJ Quade","year":"2004","unstructured":"Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004;40:97\u2013108.","journal-title":"Genes Chromosomes Cancer."},{"key":"425_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0165-4608(00)00225-9","volume":"121","author":"B Levy","year":"2000","unstructured":"Levy B, Mukherjee T, Hirschhorn K. Molecular cytogenetic analysis of uterine leiomyoma and leiomyosarcoma by comparative genomic hybridization. Cancer Genet Cytogenet. 2000;121:1\u20138.","journal-title":"Cancer Genet Cytogenet."},{"key":"425_CR42","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.cancergen.2012.04.005","volume":"205","author":"JM Bowen","year":"2012","unstructured":"Bowen JM, Cates JM, Kash S, Itani D, Gonzalez A, Huang D, et al. Genomic imbalances in benign metastasizing leiomyoma: characterization by conventional karyotypic, fluorescence in situ hybridization, and whole genome SNP array analysis. Cancer Genet. 2012;205:249\u201354.","journal-title":"Cancer Genet"},{"key":"425_CR43","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1097\/01.pas.0000213414.15633.4e","volume":"31","author":"MR Nucci","year":"2007","unstructured":"Nucci MR, Drapkin R, Dal Cin P, Fletcher CD, Fletcher JA. Distinctive cytogenetic profile in benign metastasizing leiomyoma: pathogenetic implications. Am J Surg Pathol. 2007;31:737\u201343.","journal-title":"Am J Surg Pathol."},{"key":"425_CR44","first-page":"PO.20.00040","volume":"4","author":"EA Williams","year":"2020","unstructured":"Williams EA, Sharaf R, Decker B, Werth AJ, Toma H, Montesion M, et al. CDKN2C-null leiomyosarcoma: a novel, genomically distinct class of TP53\/RB1-wild-type tumor with frequent CIC genomic alterations and 1p\/19q-codeletion. JCO Precis Oncol. 2020;4:PO.20.00040.","journal-title":"JCO Precis Oncol."},{"key":"425_CR45","unstructured":"Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. WHO classification of tumours of the central nervous system. 4th edn. Lyon: International Agency For Research On Cancer; 2016."},{"key":"425_CR46","doi-asserted-by":"publisher","first-page":"3317","DOI":"10.1158\/0008-5472.CAN-14-0772-T","volume":"74","author":"AR Grassian","year":"2014","unstructured":"Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, et al. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res. 2014;74:3317\u201331.","journal-title":"Cancer Res."},{"key":"425_CR47","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/0167-4838(88)90050-7","volume":"954","author":"SA Woods","year":"1988","unstructured":"Woods SA, Schwartzbach SD, Guest JR. Two biochemically distinct classes of fumarase in Escherichia coli. Biochim Biophys Acta. 1988;954:14\u201326.","journal-title":"Biochim Biophys Acta."},{"key":"425_CR48","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/S0092-8674(00)80574-7","volume":"96","author":"M Koegl","year":"1999","unstructured":"Koegl M, Hoppe T, Schlenker S, Ulrich HD, Mayer TU, Jentsch S. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell. 1999;96:635\u201344.","journal-title":"Cell."},{"key":"425_CR49","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S0092-8674(00)00080-5","volume":"102","author":"T Hoppe","year":"2000","unstructured":"Hoppe T, Matuschewski K, Rape M, Schlenker S, Ulrich HD, Jentsch S. Activation of a membrane-bound transcription factor by regulated ubiquitin\/proteasome-dependent processing. Cell. 2000;102:577\u201386.","journal-title":"Cell."},{"key":"425_CR50","doi-asserted-by":"publisher","first-page":"1417.","DOI":"10.3390\/molecules26051417","volume":"26","author":"P Telkoparan-Akillilar","year":"2021","unstructured":"Telkoparan-Akillilar P, Panieri E, Cevik D, Suzen S, Saso L. Therapeutic targeting of the NRF2 signaling pathway in cancer. Molecules. 2021;26:1417.","journal-title":"Molecules"},{"key":"425_CR51","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","volume":"30","author":"AM Bolger","year":"2014","unstructured":"Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114\u201320.","journal-title":"Bioinformatics."},{"key":"425_CR52","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297\u2013303.","journal-title":"Genome Res."},{"key":"425_CR53","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1093\/bioinformatics\/btp698","volume":"26","author":"H Li","year":"2010","unstructured":"Li H, Durbin R. Fast and accurate long-read alignment with Burrows-Wheeler transform. Bioinformatics. 2010;26:589\u201395.","journal-title":"Bioinformatics."},{"key":"425_CR54","doi-asserted-by":"publisher","first-page":"2580","DOI":"10.1038\/s41596-018-0052-3","volume":"13","author":"R Katainen","year":"2018","unstructured":"Katainen R, Donner I, Cajuso T, Kaasinen E, Palin K, M\u00e4kinen V, et al. Discovery of potential causative mutations in human coding and noncoding genome with the interactive software BasePlayer. Nat Protoc. 2018;13:2580\u2013600.","journal-title":"Nat Protoc."},{"key":"425_CR55","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0974-4","volume":"17","author":"W McLaren","year":"2016","unstructured":"McLaren W, Gil L, Hunt SE, Riat HS, Ritchie GR, Thormann A, et al. The ensembl variant effect predictor. Genome Biol. 2016;17:122.","journal-title":"Genome Biol."},{"key":"425_CR56","doi-asserted-by":"publisher","first-page":"e1004873","DOI":"10.1371\/journal.pcbi.1004873","volume":"12","author":"E Talevich","year":"2016","unstructured":"Talevich E, Shain AH, Botton T, Bastian BC. CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing. PLoS Comput Biol. 2016;12:e1004873.","journal-title":"PLoS Comput Biol."},{"key":"425_CR57","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15\u201321.","journal-title":"Bioinformatics."},{"key":"425_CR58","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166\u20139.","journal-title":"Bioinformatics."},{"key":"425_CR59","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","volume":"15","author":"MI Love","year":"2014","unstructured":"Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.","journal-title":"Genome Biol."},{"key":"425_CR60","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-507","volume":"12","author":"MA Kallio","year":"2011","unstructured":"Kallio MA, Tuimala JT, Hupponen T, Klemel\u00e4 P, Gentile M, Scheinin I, et al. Chipster: user-friendly analysis software for microarray and other high-throughput data. BMC Genomics. 2011;12:507.","journal-title":"BMC Genomics."},{"key":"425_CR61","doi-asserted-by":"publisher","first-page":"W77","DOI":"10.1093\/nar\/gkt439","volume":"41","author":"J Wang","year":"2013","unstructured":"Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013;41:W77\u201383. (web Server issue).","journal-title":"Nucleic Acids Res."},{"key":"425_CR62","doi-asserted-by":"publisher","unstructured":"Broad Institute TCGA Genome Data Analysis Center: Firehose stddata__2016_01_28 run. Broad Institute of MIT and Harvard. https:\/\/doi.org\/10.7908\/C11G0KM9. http:\/\/gdac.broadinstitute.org\/runs\/stddata__2016_01_28\/data\/. 2016.","DOI":"10.7908\/C11G0KM9"},{"key":"425_CR63","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1056\/NEJMp1607591","volume":"375","author":"RL Grossman","year":"2016","unstructured":"Grossman RL, Heath AP, Ferretti V, Varmus HE, Lowy DR, Kibbe WA, et al. Toward a shared vision for cancer genomic data. N. Engl J Med. 2016;375:1109\u201312.","journal-title":"N. Engl J Med."},{"key":"425_CR64","doi-asserted-by":"publisher","first-page":"3940","DOI":"10.1093\/bioinformatics\/bti623","volume":"21","author":"T Sing","year":"2005","unstructured":"Sing T, Sander O, Beerenwinkel N, Lengauer T. ROCR: visualizing classifier performance in R. Bioinformatics. 2005;21:3940\u201341.","journal-title":"Bioinformatics."},{"key":"425_CR65","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1158\/2159-8290.CD-17-0321","volume":"8","author":"MT Chang","year":"2018","unstructured":"Chang MT, Bhattarai TS, Schram AM, Bielski CM, Donoghue MTA, Jonsson P, et al. Accelerating discovery of functional mutant alleles in cancer. Cancer Discov. 2018;8:174\u201383.","journal-title":"Cancer Discov."},{"key":"425_CR66","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1101\/gr.239244.118","volume":"28","author":"A Mayakonda","year":"2018","unstructured":"Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28:1747\u201356.","journal-title":"Genome Res."},{"key":"425_CR67","doi-asserted-by":"publisher","first-page":"1779","DOI":"10.1038\/ng.3984","volume":"49","author":"RM Meyers","year":"2017","unstructured":"Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49:1779\u201384.","journal-title":"Nat Genet"},{"key":"425_CR68","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.cell.2017.06.010","volume":"170","author":"A Tsherniak","year":"2017","unstructured":"Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a cancer dependency map. Cell. 2017;170:564\u2013576.e516.","journal-title":"Cell."},{"key":"425_CR69","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.cell.2019.12.023","volume":"180","author":"DP Nusinow","year":"2020","unstructured":"Nusinow DP, Szpyt J, Ghandi M, Rose CM, McDonald ER 3rd, Kalocsay M, et al. Quantitative proteomics of the cancer cell line encyclopedia. Cell. 2020;180:387\u2013402.e316.","journal-title":"Cell."},{"key":"425_CR70","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.","journal-title":"Nucleic Acids Res."},{"key":"425_CR71","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139\u201340.","journal-title":"Bioinformatics."},{"key":"425_CR72","doi-asserted-by":"publisher","first-page":"D613","DOI":"10.1093\/nar\/gkaa1024","volume":"49","author":"M Martens","year":"2021","unstructured":"Martens M, Ammar A, Riutta A, Waagmeester A, Slenter DN, Hanspers K, et al. WikiPathways: connecting communities. Nucleic Acids Res. 2021;49:D613\u201321.","journal-title":"Nucleic Acids Res."},{"key":"425_CR73","doi-asserted-by":"publisher","first-page":"7975","DOI":"10.1158\/0008-5472.CAN-08-1401","volume":"68","author":"A Singh","year":"2008","unstructured":"Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, et al. RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res. 2008;68:7975\u201384.","journal-title":"Cancer Res"}],"container-title":["Oncogenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41389-022-00425-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41389-022-00425-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41389-022-00425-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,7]],"date-time":"2022-09-07T04:03:58Z","timestamp":1662523438000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41389-022-00425-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,7]]},"references-count":73,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["425"],"URL":"https:\/\/doi.org\/10.1038\/s41389-022-00425-3","relation":{},"ISSN":["2157-9024"],"issn-type":[{"value":"2157-9024","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,7]]},"assertion":[{"value":"25 January 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 August 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"52"}}