{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T22:42:30Z","timestamp":1790548950755,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,11,7]],"date-time":"2017-11-07T00:00:00Z","timestamp":1510012800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["11M9814\/16N"],"award-info":[{"award-number":["11M9814\/16N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2018,3,15]]},"abstract":"<jats:p>Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome\u2010wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting <jats:italic>TP53<\/jats:italic>, <jats:italic>RB1<\/jats:italic>, <jats:italic>PTEN<\/jats:italic>, <jats:italic>MED12<\/jats:italic>, <jats:italic>YWHAE<\/jats:italic> and <jats:italic>VIPR2<\/jats:italic> were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K\/AKT\/mTOR, estrogen\u2010mediated S\u2010phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (<jats:italic>CCNE1<\/jats:italic>, <jats:italic>TDO2<\/jats:italic>), as well as deletions and reduced expression of tumor suppressor genes (<jats:italic>PTEN<\/jats:italic>, <jats:italic>PRDM16<\/jats:italic>). Overall, it emerged that the most frequently affected gene in our uLMS samples was <jats:italic>VIPR2<\/jats:italic> (96%). Interestingly, <jats:italic>VIPR2<\/jats:italic> deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR\u2009=\u20094.5, CI\u2009=\u20091.4\u201314.3, <jats:italic>p<\/jats:italic>\u2009=\u20091.2E\u201002), while VIPR2 protein expression was reduced in uLMS <jats:italic>vs<\/jats:italic>. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK\u2010UT\u20101 uLMS cell proliferation in a dose\u2010dependent manner. These data suggest that <jats:italic>VIPR2<\/jats:italic>, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.<\/jats:p>","DOI":"10.1002\/ijc.31129","type":"journal-article","created":{"date-parts":[[2017,10,24]],"date-time":"2017-10-24T07:47:01Z","timestamp":1508831221000},"page":"1230-1243","source":"Crossref","is-referenced-by-count":76,"title":["Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways"],"prefix":"10.1002","volume":"142","author":[{"given":"Tine","family":"Cuppens","sequence":"first","affiliation":[{"name":"Department of Oncology, Gynecologic Oncology KU Leuven (University of Leuven) Leuven 3000 Belgium"},{"name":"VIB Center for Cancer Biology, VIB Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Moisse","sequence":"additional","affiliation":[{"name":"Laboratory for Translational 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