Publication Date
1-1-2025
Journal
Nature Genetics
DOI
10.1038/s41588-024-02014-z
PMID
39753768
PMCID
PMC11735403
PubMedCentral® Posted Date
1-3-2025
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Medulloblastoma, Transcription Factors, Humans, Animals, Mice, Cerebellar Neoplasms, Gene Expression Regulation, Neoplastic, Cell Proliferation, Hedgehog Proteins, Mutation, Loss of Function Mutation, Embryonic Structures, Metencephalon, Epigenomics, Oncogenes, CNS cancer, Mutagenesis
Abstract
Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that ZIC1 exhibits loss-of-function (LOF) somatic events in group 4 (G4) medulloblastoma through recurrent point mutations, subchromosomal deletions and mono-allelic epigenetic repression (60% of G4 medulloblastoma). In contrast, highly similar SHH medulloblastoma exhibits distinct and diametrically opposed gain-of-function mutations and copy number gains (20% of SHH medulloblastoma). Overexpression of ZIC1 suppresses the growth of group 3 medulloblastoma models, whereas it promotes the proliferation of SHH medulloblastoma precursor cells. SHH medulloblastoma ZIC1 mutants show increased activity versus wild-type ZIC1, whereas G4 medulloblastoma ZIC1 mutants exhibit LOF phenotypes. Distinct ZIC1 mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that ZIC1 is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying ZIC1 as an exquisitely context-dependent driver gene in medulloblastoma.
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Genetics Commons, Genomics Commons, Medical Genetics Commons, Mental and Social Health Commons, Neurology Commons, Neurosciences Commons, Oncology Commons
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