Publication Date
10-7-2023
Journal
Nature Communications
DOI
10.1038/s41467-023-41926-y
PMID
37805627
PMCID
PMC10560290
PubMedCentral® Posted Date
10-7-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Hedgehog Proteins, Meningioma, Ligands, Signal Transduction, Meningeal Neoplasms, Cancer genomics, Molecular medicine, CNS cancer
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.
Included in
Genomics Commons, Medical Genetics Commons, Mental and Social Health Commons, Neurology Commons, Neurosciences Commons, Oncology Commons