biostudies-literatureLee JJYU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)EIF | Stand Up To Cancer (SU2C)U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)NCI NIH HHSNINDS NIH HHSWellcome Trust88-102https://www.ebi.ac.uk/biostudies/studies/S-EPMC11735403biostudies-literatureUnknown57(1)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 mutanNature geneticsZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.PMC11735403R01 CA255369SU2C-AACR-DT1113SU2C-AACR-DT-19-15R01 CA159859R01NS1061551R01CA270785-01A1R37 NS095733R01 CA270785R01CA255369P01 CA096832R01 NS106155Mount CWMorrissy SKool MSuva MLLivingston BGFrench PJHendriske LDDas Gupta NKorshunov APhillips JJThompson RCKros JMPerek-Polnik MBatts MVisvanathan AKim SKWu XZadeh GTaylor MDSaad AGNorthcott PAGarzia LGallo MBendel AAbeysundara NCavalli FMGPalotta JBailey SGrajkowska WALee JJYTominaga TRa YSHuang LFWeiss WAMack SCSingh SKKlekner AFarooq HMichealraj KALiu MRamaswamy VSuzuki HWang EYLupien MRichman CMBognar LKenney AMHaldipur PLoukides JFong VPollack IFJabado NCho BKYou ZMillen KJCooper MKHadley JLach BLuu BSuarez RDaniels CErickson AWLee JYWang KCDai SRasnitsyn ALeary SESChico Ponce de Leon FHamilton RLTao RPerezpena-Diazconti MfalseZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.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 mutan2025-01-01T00:00:00Z2025 Jan2026-06-01T21:07:11.98Z2025-04-06T01:16:03.978ZS-EPMC117354033975376810.1038/s41588-024-02014-z