Nature genetics · 2025

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

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

Аннотация

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.

Предметные рубрики MeSH

Medulloblastoma Transcription Factors Humans Animals Cerebellar Neoplasms Mice Gene Expression Regulation, Neoplastic Mutation Cell Line, Tumor Loss of Function Mutation Metencephalon

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH