Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas
-
Published:2023-10-07
Issue:1
Volume:14
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Youngblood Mark W.ORCID, Erson-Omay Zeynep, Li Chang, Najem HindaORCID, Coșkun Süleyman, Tyrtova Evgeniya, Montejo Julio D.ORCID, Miyagishima Danielle F.ORCID, Barak Tanyeri, Nishimura SayokoORCID, Harmancı Akdes Serin, Clark Victoria E., Duran DanielORCID, Huttner Anita, Avşar Timuçin, Bayri Yasar, Schramm Johannes, Boetto Julien, Peyre MatthieuORCID, Riche Maximilien, Goldbrunner Roland, Amankulor Nduka, Louvi AngelikiORCID, Bilgüvar Kaya, Pamir M. Necmettin, Özduman Koray, Kilic Türker, Knight James R.ORCID, Simon Matthias, Horbinski CraigORCID, Kalamarides Michel, Timmer Marco, Heimberger Amy B.ORCID, Mishra-Gorur KetuORCID, Moliterno Jennifer, Yasuno KatsuhitoORCID, Günel MuratORCID
Abstract
AbstractHedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway in neoplasia.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference91 articles.
1. Goutagny, S. et al. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol. 24, 184–189 (2014). 2. Nassiri, F. et al. A clinically applicable integrative molecular classification of meningiomas. Nature 597, 119–125 (2021). 3. Youngblood, M. W. et al. Associations of meningioma molecular subgroup and tumor recurrence. Neuro Oncol. 23, 783–794 (2021). 4. Choudhury, A. et al. Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities. Nat. Genet. 54, 649–659 (2022). 5. Sahm, F. et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 18, 682–694 (2017).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|