Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas
Mark W. Youngblood, E. Zeynep Erson‐Omay, Chang Li, Hinda Najem, Süleyman Coşkun, Evgeniya Tyrtova, Julio D. Montejo, Danielle Miyagishima, Tanyeri Barak, S. Nishimura, Akdes Serin Harmancı, Victoria Clark, Daniel Durán, Anita Hüttner, Timuçin Avşar, Yaşar Bayri, Johannes Schramm, Julien Boetto, Matthieu Peyre, Maximilien Riche, Roland Goldbrunner, Nduka Amankulor, Angeliki Louvi, Kaya Bilgüvar, M. Necmettin Pamir, Koray Özduman, Türker Kılıç, James Knight, Matthias Simon, Craig Horbinski, Michel Kalamarides, Marco Timmer, Amy B. Heimberger, Ketu Mishra-Gorur, Jennifer Moliterno, Katsuhito Yasuno, Murat Günel
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.