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
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Nat Genet. 2025 Jan;57(1):88-102. doi: 10.1038/s41588-024-02014-z. Epub 2025 Jan 3.
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.
转录因子是常见的癌症驱动基因，基于精确的起源细胞表现出显著的特异性。我们证明，ZIC1在4组（G4）髓母细胞瘤中通过复发性点突变、亚染色体缺失和单等位基因表观遗传抑制（占G4髓母细胞瘤的60%）表现出功能丧失（LOF）体细胞事件。相比之下，高度相似的SHH髓母细胞瘤表现出截然不同且完全相反的功能获得性突变和拷贝数增加（占SHH髓母细胞瘤的20%）。ZIC1的过表达抑制3组髓母细胞瘤模型的生长，而促进SHH髓母细胞瘤前体细胞的增殖。SHH髓母细胞瘤ZIC1突变体相对于野生型ZIC1显示出活性增加，而G4髓母细胞瘤ZIC1突变体表现出LOF表型。不同的ZIC1突变以完全相反的方式影响菱唇细胞，这表明ZIC1在正常和转化的菱唇中都是关键的发育转录调节因子，并将ZIC1鉴定为髓母细胞瘤中一个高度依赖背景的驱动基因。
