ArticleNature genetics2025
ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip.
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Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11citing papers in PubMed
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Who cites it
11 citing papers in PubMed.
- Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency.Nature genetics · 2026Article
- Expanding the phenotypic spectrum associated with ZIC1 variants: A neurodevelopmental disorder with and without craniosynostosis.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Multi-omics integration reveals pan-cancer roles of ZIC family genes in prognosis, immune microenvironment remodeling, and therapeutic vulnerability.Discover oncology · 2026Article
- Temporal neuronal differentiation programs safeguard neuronal diversity.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Machine learning-based identification of extracellular matrix-related prognostic subtypes in SHH-activated medulloblastoma.Discover oncology · 2026Article
- Neurooncology: 2026 update.Free neuropathology · 2026Review
- Human stem cell models for group 3 medulloblastoma uncover JARID1B as a regulator of the chromatin landscape.bioRxiv : the preprint server for biology · 2025Article
- Opposite patterns of association of TWIST1 expression with patient survival in SHH and Group 4 medulloblastoma.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2025Article
- Advancing Medulloblastoma Therapy in Pediatrics: Integrative Molecular Classification and Emerging Treatments.Brain sciences · 2025Review
- GABAergic Influences on Medulloblastoma.Brain sciences · 2025Review
- Metastatic medulloblastoma remodels the local leptomeningeal microenvironment to promote further metastatic colonization and growth.Nature cell biology · 2025Article
Corrections and comments
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Authors and funding
71 authors.
John J Y Lee *Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Ran Tao *Center of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Zhen You *Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.ORCID 0000-0002-0578-4823
Parthiv HaldipurNorcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Anders W EricksonDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.ORCID 0000-0002-6134-7812
Hamza FarooqDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Liam D HendriskeDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Namal AbeysundaraThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Cory M RichmanThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Evan Y WangThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID 0000-0001-7984-3147
Neha Das GuptaCenter of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Jennifer HadleyCenter of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0003-1918-747X
Melissa BattsCenter of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0009-0007-3130-6570
Christopher W MountDepartment of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Xiaochong WuThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Alex RasnitsynThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Swneke BaileyThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Florence M G CavalliInserm, Paris, France.
Sorana MorrissyThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID 0000-0001-8526-562X
Livia GarziaDepartment of Surgery, McGill University and RI-MUHC Cancer Research Program, Montreal, Quebec, Canada.ORCID 0000-0002-5016-0753
Kulandaimanuvel Antony MichealrajThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Abhi VisvanathanThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Vernon FongDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Jonelle PalottaThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Raul SuarezThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Bryn G LivingstonDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.ORCID 0000-0003-4947-0081
Miao LiuDepartment of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
Betty LuuThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Craig DanielsThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
James LoukidesThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.
Anne BendelDepartment of Pediatric Hematology-Oncology, Children's Hospital of Minnesota, Minneapolis, MN, USA.
Pim J FrenchDepartment of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.ORCID 0000-0002-0668-9529
Johan M KrosDepartment of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands.ORCID 0000-0002-4727-0724
Andrey KorshunovClinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Marcel KoolDivision of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Research Consortium (DKTK), Heidelberg, Germany.
Fernando Chico Ponce de LeónDepartment of Neurosurgery, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.
Mario Perezpeña-DiazcontiDepartment of Pathology, Instituto Nacional de Pediatria, Mexico City, Mexico.ORCID 0000-0002-1007-7744
Boleslaw LachDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
Sheila K SinghDepartment of Surgery, McMaster University, Hamilton, Ontario, Canada.ORCID 0000-0003-1272-5300
Sarah E S LearyCancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA, USA.ORCID 0000-0003-0225-6184
Byung-Kyu ChoDivision of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.
Seung-Ki KimDivision of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.
Kyu-Chang WangNeuro-Oncology Clinic, National Cancer Center, Goyang, Republic of Korea.
Ji-Yeoun LeeDivision of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.
Teiji TominagaDepartment of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
William A WeissDepartment of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Joanna J PhillipsDepartment of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.ORCID 0000-0002-3789-8120
Shizhong DaiDepartment of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
Gelareh ZadehPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.ORCID 0000-0002-6637-4502
Ali G SaadDepartment of Pediatric Pathology and Neuropathology, University of Miami Miller School of Medicine, Miami, FL, USA.
László BognárDepartment of Neurosurgery, University of Debrecen, Debrecen, Hungary.
Almos KleknerDepartment of Neurosurgery, University of Debrecen, Debrecen, Hungary.
Ian F PollackDepartment of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Ronald L HamiltonDepartment of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.ORCID 0000-0002-6802-1102
Young-Shin RaDepartment of Neurosurgery, University of Ulsan Asan Medical Center, Ulsan, Republic of Korea.
Wieslawa A GrajkowskaDepartment of Pathology, The Children's Memorial Health Institute, Warsaw, Poland.
Marta Perek-PolnikDepartment of Oncology, The Children's Memorial Health Institute, Warsaw, Poland.
Reid C ThompsonDepartment of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA.
Anna M KenneyDepartment of Pediatrics, Emory University, Atlanta, GA, USA.ORCID 0000-0001-8323-0618
Michael K CooperDepartment of Neurology, Vanderbilt Medical Center, Nashville, TN, USA.
Stephen C MackCenter of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0001-9620-4742
Nada JabadoDivision of Experimental Medicine, McGill University, Montreal, Quebec, Canada.ORCID 0000-0003-2485-3692
Mathieu LupienDepartment of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Marco GalloDepartment of Pediatrics, Baylor College of Medicine, Houston, TX, USA.ORCID 0000-0002-8451-8207
Vijay RamaswamyThe Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario, Canada.ORCID 0000-0002-6557-895X
Mario L SuvaDepartment of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-9898-5351
Hiromichi SuzukiDivision of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.ORCID 0000-0002-8858-0294
Kathleen J MillenNorcliffe Foundation Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.ORCID 0000-0001-9978-675X
L Frank HuangDepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. huang.frank@mayo.edu.ORCID 0000-0002-0322-6078
Paul A NorthcottCenter of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA. paul.northcott@stjude.org.ORCID 0000-0002-1220-5252
Michael D TaylorDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. mdt.cns@gmail.com.ORCID 0000-0001-7009-3466
Funding
The DNA Damage Response and Tumorigenesis in the BrainP01CA096832 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI BAKER, SUZANNE J. · 2003 to 2025
$38.0MMouse models to discover new drivers of medulloblastomaR01CA159859 · NCI · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · PI Michael D. Taylor, WILLIAM A WEISS · 2011 to 2026
$10.4MPathological Mechanisms of Human Cerebellar MalformationsR37NS095733 · NINDS · SEATTLE CHILDREN'S HOSPITAL · PI Kathleen Joyce Millen · 2021 to 2026
$5.5MCCL2 and CCR2 as metastatic drivers and therapeutic targets in medulloblastomaR01CA255369 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GARZIA, LIVIA, TAYLOR, MICHAEL D. · 2021 to 2025
$3.9MPrevention and treatment of lethal metastases in group 3 medulloblastomaR01NS106155 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI TAYLOR, MICHAEL D., WEISS, WILLIAM A · 2018 to 2022
$2.8MMapping the Cerebellar Origins of Medulloblastoma SubgroupsR01CA270785 · NCI · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI Paul Northcott · 2023 to 2026
$2.8MEIF | Stand Up To Cancer (SU2C) SU2C-AACR-DT1113EIF | Stand Up To Cancer (SU2C) SU2C-AACR-DT-19-15NCI NIH HHS P01 CA096832NCI NIH HHS R01 CA159859NCI NIH HHS R01 CA255369NCI NIH HHS R01 CA270785NINDS NIH HHS R01 NS106155NINDS NIH HHS R37 NS095733U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) 1R01CA270785-01A1U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA255369U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS106155Wellcome Trust
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.
Indexed as
Cerebellar NeoplasmsMedulloblastomaTranscription FactorsAnimalsCell Line, TumorGene Expression Regulation, NeoplasticHumansLoss of Function MutationMetencephalonMiceMutationTranscription FactorsZIC1 protein, human
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