ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip
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 Gupta, Jennifer Hadley, Melissa Batts, Christopher Mount, Xiaochong Wu, Alex Rasnitsyn, Swneke D. Bailey, Florence M.G. Cavalli, A. Sorana Morrissy, Livia Garzia, Kulandaimanuvel Antony Michealraj, Abhi Visvanathan, Vernon Fong, Jonelle Palotta, Raúl A. Suárez, Bryn Livingston, Liu Miao, Betty Luu, Craig Daniels, James Loukides, Anne Bendel, Pim J. French, Johan M. Kros, Andrey Korshunov, Marcel Kool, Fernando Chico Ponce de León, Mario Pérezpeña-Díazconti, Bolesław Lach, Sheila K. Singh, Sarah 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, Álmos Klekner, Ian F. Pollack, Ronald L. Hamilton, Young‐Shin Ra, Wiesława Grajkowska, Marta Perek‐Polnik, Reid C. Thompson, Anna Marie Kenney, Michael K. Cooper, Stephen C. Mack, Nada Jabado, Mathieu Lupien, Marco Gallo, Vijay Ramaswamy, Mario L. Suvà, Hiromichi Suzuki, Kathleen J. Millen, Lei Huang, Paul A. Northcott, Michael D. Taylor
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.