Nature Communications (Oct 2023)
Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas
- Mark W. Youngblood,
- Zeynep Erson-Omay,
- Chang Li,
- Hinda Najem,
- Süleyman Coșkun,
- Evgeniya Tyrtova,
- Julio D. Montejo,
- Danielle F. Miyagishima,
- Tanyeri Barak,
- Sayoko Nishimura,
- Akdes Serin Harmancı,
- Victoria E. Clark,
- Daniel Duran,
- Anita Huttner,
- Timuçin Avşar,
- Yasar Bayri,
- Johannes Schramm,
- Julien Boetto,
- Matthieu Peyre,
- Maximilien Riche,
- Roland Goldbrunner,
- Nduka Amankulor,
- Angeliki Louvi,
- Kaya Bilgüvar,
- M. Necmettin Pamir,
- Koray Özduman,
- Türker Kilic,
- James R. Knight,
- Matthias Simon,
- Craig Horbinski,
- Michel Kalamarides,
- Marco Timmer,
- Amy B. Heimberger,
- Ketu Mishra-Gorur,
- Jennifer Moliterno,
- Katsuhito Yasuno,
- Murat Günel
Affiliations
- Mark W. Youngblood
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Zeynep Erson-Omay
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Chang Li
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Hinda Najem
- Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University
- Süleyman Coșkun
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Evgeniya Tyrtova
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Julio D. Montejo
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Danielle F. Miyagishima
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Tanyeri Barak
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Sayoko Nishimura
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Akdes Serin Harmancı
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Victoria E. Clark
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Daniel Duran
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Anita Huttner
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Timuçin Avşar
- Department of Neurosurgery, Bahcesehir University, School of Medicine
- Yasar Bayri
- Department of Neurosurgery, Marmara University School of Medicine
- Johannes Schramm
- University of Bonn Medical School
- Julien Boetto
- Department of Neurosurgery, Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université
- Matthieu Peyre
- Department of Neurosurgery, Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université
- Maximilien Riche
- Department of Neurosurgery, Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université
- Roland Goldbrunner
- Center for Neurosurgery, University Hospital of Cologne
- Nduka Amankulor
- Department of Neurosurgery, University of Pennsylvania
- Angeliki Louvi
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Kaya Bilgüvar
- Yale Program in Brain Tumor Research, Yale School of Medicine
- M. Necmettin Pamir
- Department of Neurosurgery, Acibadem Mehmet Ali Aydınlar University, School of Medicine
- Koray Özduman
- Department of Neurosurgery, Acibadem Mehmet Ali Aydınlar University, School of Medicine
- Türker Kilic
- Department of Neurosurgery, Bahcesehir University, School of Medicine
- James R. Knight
- Yale Center for Genome Analysis, Yale University West Campus
- Matthias Simon
- University of Bonn Medical School
- Craig Horbinski
- Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University
- Michel Kalamarides
- Department of Neurosurgery, Hopital Pitie-Salpetriere, AP-HP & Sorbonne Université
- Marco Timmer
- Center for Neurosurgery, University Hospital of Cologne
- Amy B. Heimberger
- Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University
- Ketu Mishra-Gorur
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Jennifer Moliterno
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Katsuhito Yasuno
- Yale Program in Brain Tumor Research, Yale School of Medicine
- Murat Günel
- Yale Program in Brain Tumor Research, Yale School of Medicine
- DOI
- https://doi.org/10.1038/s41467-023-41926-y
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 16
Abstract
Abstract Hedgehog 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.
