Journal Article

DKFZ-2025-00060

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip

Lee, J. J. Y. ; Tao, R. ; You, Z. ; Haldipur, P. ; Erickson, A. W. ; Farooq, H. ; Hendriske, L. D. ; Abeysundara, N. ; Richman, C. M. ; Wang, E. Y. ; Das Gupta, N. ; Hadley, J. ; Batts, M. ; Mount, C. W. ; Wu, X. ; Rasnitsyn, A. ; Bailey, S. ; Cavalli, F. M. G. ; Morrissy, S. ; Garzia, L. ; Michealraj, K. A. ; Visvanathan, A. ; Fong, V. ; Palotta, J. ; Suarez, R. ; Livingston, B. G. ; Liu, M. ; Luu, B. ; Daniels, C. ; Loukides, J. ; Bendel, A. ; French, P. J. ; Kros, J. M. ; Korshunov, A.DKFZ* ; Kool, M.DKFZ* ; Chico Ponce de León, F. ; Perezpeña-Diazconti, M. ; Lach, B. ; Singh, S. K. ; Leary, S. E. S. ; Cho, B.-K. ; Kim, S.-K. ; Wang, K.-C. ; Lee, J.-Y. ; Tominaga, T. ; Weiss, W. A. ; Phillips, J. J. ; Dai, S. ; Zadeh, G. ; Saad, A. G. ; Bognár, L. ; Klekner, A. ; Pollack, I. F. ; Hamilton, R. L. ; Ra, Y.-s. ; Grajkowska, W. A. ; Perek-Polnik, M. ; Thompson, R. C. ; Kenney, A. M. ; Cooper, M. K. ; Mack, S. C. ; Jabado, N. ; Lupien, M. ; Gallo, M. ; Ramaswamy, V. ; Suva, M. L. ; Suzuki, H. ; Millen, K. J. ; Huang, L. F. ; Northcott, P. A. ; Taylor, M. D.

2025
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-024-02014-z

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.

Note: 2025 Jan;57(1):88-102

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)
3. KKE Neuropathologie (B300)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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