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 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

doi:10.1038/s41588-024-02014-z

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 Das Gupta, Jennifer Hadley, Melissa Batts, Christopher W. Mount, Xiaochong Wu, Alex Rasnitsyn, Swneke Bailey, Florence M.G. Cavalli, Sorana Morrissy, Livia GarziaKulandaimanuvel 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	1749
Pages (from-to)	88-102
Number of pages	15
Journal	Nature genetics
Volume	57
Issue number	1
Early online date	3 Jan 2025
DOIs	https://doi.org/10.1038/s41588-024-02014-z
Publication status	Published - Jan 2025

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s41588-024-02014-zFinal published version, 11.3 MBLicence: CC BY

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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., ... Taylor, M. D. (2025). ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip. Nature genetics, 57(1), 88-102. Article 1749. https://doi.org/10.1038/s41588-024-02014-z

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title = "ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip",

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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jan,

doi = "10.1038/s41588-024-02014-z",

language = "English",

volume = "57",

pages = "88--102",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "1",

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Lee, JJY, Tao, R, You, Z, Haldipur, P, Erickson, AW, Farooq, H, Hendriske, LD, Abeysundara, N, Richman, CM, Wang, EY, Das Gupta, N, Hadley, J, Batts, M, Mount, CW, Wu, X, Rasnitsyn, A, Bailey, S, Cavalli, FMG, Morrissy, S, Garzia, L, Michealraj, KA, Visvanathan, A, Fong, V, Palotta, J, Suarez, R, Livingston, BG, Liu, M, Luu, B, Daniels, C, Loukides, J, Bendel, A, French, PJ, Kros, JM, Korshunov, A, Kool, M, Chico Ponce de León, F, Perezpeña-Diazconti, M, Lach, B, Singh, SK, Leary, SES, Cho, BK, Kim, SK, Wang, KC, Lee, JY, Tominaga, T, Weiss, WA, Phillips, JJ, Dai, S, Zadeh, G, Saad, AG, Bognár, L, Klekner, A, Pollack, IF, Hamilton, RL, Ra, YS, Grajkowska, WA, Perek-Polnik, M, Thompson, RC, Kenney, AM, Cooper, MK, Mack, SC, Jabado, N, Lupien, M, Gallo, M, Ramaswamy, V, Suva, ML, Suzuki, H, Millen, KJ, Huang, LF, Northcott, PA & Taylor, MD 2025, 'ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip', Nature genetics, vol. 57, no. 1, 1749, pp. 88-102. https://doi.org/10.1038/s41588-024-02014-z

TY - JOUR

T1 - ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip

AU - Lee, John J.Y.

AU - Tao, Ran

AU - You, Zhen

AU - Haldipur, Parthiv

AU - Erickson, Anders W.

AU - Farooq, Hamza

AU - Hendriske, Liam D.

AU - Abeysundara, Namal

AU - Richman, Cory M.

AU - Wang, Evan Y.

AU - Das Gupta, Neha

AU - Hadley, Jennifer

AU - Batts, Melissa

AU - Mount, Christopher W.

AU - Wu, Xiaochong

AU - Rasnitsyn, Alex

AU - Bailey, Swneke

AU - Cavalli, Florence M.G.

AU - Morrissy, Sorana

AU - Garzia, Livia

AU - Michealraj, Kulandaimanuvel Antony

AU - Visvanathan, Abhi

AU - Fong, Vernon

AU - Palotta, Jonelle

AU - Suarez, Raul

AU - Livingston, Bryn G.

AU - Liu, Miao

AU - Luu, Betty

AU - Daniels, Craig

AU - Loukides, James

AU - Bendel, Anne

AU - French, Pim J.

AU - Kros, Johan M.

AU - Korshunov, Andrey

AU - Kool, Marcel

AU - Chico Ponce de León, Fernando

AU - Perezpeña-Diazconti, Mario

AU - Lach, Boleslaw

AU - Singh, Sheila K.

AU - Leary, Sarah E.S.

AU - Cho, Byung Kyu

AU - Kim, Seung Ki

AU - Wang, Kyu Chang

AU - Lee, Ji Yeoun

AU - Tominaga, Teiji

AU - Weiss, William A.

AU - Phillips, Joanna J.

AU - Dai, Shizhong

AU - Zadeh, Gelareh

AU - Saad, Ali G.

AU - Bognár, László

AU - Klekner, Almos

AU - Pollack, Ian F.

AU - Hamilton, Ronald L.

AU - Ra, Young Shin

AU - Grajkowska, Wieslawa A.

AU - Perek-Polnik, Marta

AU - Thompson, Reid C.

AU - Kenney, Anna M.

AU - Cooper, Michael K.

AU - Mack, Stephen C.

AU - Jabado, Nada

AU - Lupien, Mathieu

AU - Gallo, Marco

AU - Ramaswamy, Vijay

AU - Suva, Mario L.

AU - Suzuki, Hiromichi

AU - Millen, Kathleen J.

AU - Huang, L. Frank

AU - Northcott, Paul A.

AU - Taylor, Michael D.

PY - 2025/1

Y1 - 2025/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41588-024-02014-z

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SN - 1061-4036

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SP - 88

EP - 102

JO - Nature genetics

JF - Nature genetics

IS - 1

M1 - 1749

ER -

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

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