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<p>Transcription factors are frequent cancer driver genes, exhibiting noted specificity based on the precise cell of origin. We demonstrate that <i>ZIC1</i> 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 <i>ZIC1</i> mutations affect cells of the rhombic lip in diametrically opposed ways, suggesting that <i>ZIC1</i> is a critical developmental transcriptional regulator in both the normal and transformed rhombic lip and identifying <i>ZIC1</i> as an exquisitely context-dependent driver gene in medulloblastoma.</p>

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ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月3日

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  • John J. Y. Lee,
  • Ran Tao,
  • Zhen You,
  • Parthiv Haldipur,
  • Anders W. Erickson,
  • Hamza Farooq,
  • Liam D. Hendriske,
  • Namal Abeysundara,
  • Cory M. Richman,
  • Evan Y. Wang,
  • Neha Das Gupta,
  • Jennifer Hadley,
  • Melissa Batts,
  • Christopher W. Mount,
  • Xiaochong Wu,
  • Alex Rasnitsyn,
  • Swneke Bailey,
  • Florence M. G. Cavalli,
  • Sorana Morrissy,
  • Livia Garzia,
  • Kulandaimanuvel Antony Michealraj,
  • Abhi Visvanathan,
  • Vernon Fong,
  • Jonelle Palotta,
  • Raul Suarez,
  • Bryn G. Livingston,
  • Miao Liu,
  • Betty Luu,
  • Craig Daniels,
  • James Loukides,
  • Anne Bendel,
  • Pim J. French,
  • Johan M. Kros,
  • Andrey Korshunov,
  • Marcel Kool,
  • Fernando Chico Ponce de León,
  • Mario Perezpeña-Diazconti,
  • Boleslaw Lach,
  • Sheila K. Singh,
  • Sarah E. S. Leary,
  • Byung-Kyu Cho,
  • Seung-Ki Kim,
  • Kyu-Chang Wang,
  • Ji-Yeoun Lee,
  • Teiji Tominaga,
  • William A. Weiss,
  • Joanna J. Phillips,
  • Shizhong Dai,
  • Gelareh Zadeh,
  • Ali G. Saad,
  • László Bognár,
  • Almos Klekner,
  • Ian F. Pollack,
  • Ronald L. Hamilton,
  • Young-shin Ra,
  • Wieslawa A. Grajkowska,
  • Marta Perek-Polnik,
  • Reid C. Thompson,
  • Anna M. Kenney,
  • Michael K. Cooper,
  • Stephen C. Mack,
  • Nada Jabado,
  • Mathieu Lupien,
  • Marco Gallo,
  • Vijay Ramaswamy,
  • Mario L. Suva,
  • Hiromichi Suzuki,
  • Kathleen J. Millen,
  • L. Frank Huang,
  • Paul A. Northcott,
  • Michael D. Taylor

摘要

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.