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.
- ZIC1 is a context-dependent medulloblastoma driver in the rhombic lip
- John J Y Lee - Center for Cancer ResearchRan Tao - St. Jude Children's Research HospitalZhen You - Mayo ClinicParthiv Haldipur - Norcliffe FoundationAnders W Erickson - Hospital for Sick ChildrenHamza Farooq - University of TorontoLiam D Hendriske - Hospital for Sick ChildrenNamal Abeysundara - SickKids FoundationCory M Richman - University of TorontoEvan Y Wang - University of TorontoNeha Das Gupta - St. Jude Children's Research HospitalJennifer Hadley - St. Jude Children's Research HospitalMelissa Batts - St. Jude Children's Research HospitalChristopher W Mount - Broad InstituteXiaochong Wu - SickKids FoundationAlex Rasnitsyn - Hospital for Sick ChildrenSwneke Bailey - Hospital for Sick ChildrenFlorence M G Cavalli - Université Paris Sciences et LettresSorana Morrissy - University of CalgaryLivia Garzia - McGill UniversityKulandaimanuvel Antony Michealraj - Hospital for Sick ChildrenAbhi Visvanathan - Hospital for Sick ChildrenVernon Fong - Hospital for Sick ChildrenJonelle Palotta - Hospital for Sick ChildrenRaul Suarez - Hospital for Sick ChildrenBryn G Livingston - Hospital for Sick ChildrenMiao Liu - Mayo ClinicBetty Luu - Hospital for Sick ChildrenCraig Daniels - Baylor College of MedicineJames Loukides - Hospital for Sick ChildrenAnne Bendel - Children’s Minnesota - St. Paul HospitalPim J French - Erasmus MCJohan M Kros - Erasmus MCAndrey Korshunov - German Cancer Research CenterMarcel Kool - German Cancer Research CenterFernando Chico Ponce de León - Hospital Infantil de México Federico GómezMario Perezpeña-Diazconti - Instituto Nacional de PediatriaBoleslaw Lach - McMaster UniversitySheila K Singh - McMaster UniversitySarah E S Leary - Seattle Children's HospitalByung-Kyu Cho - Seoul National University Children's HospitalSeung-Ki Kim - Seoul National University Children's HospitalKyu-Chang Wang - Montreal Neurological Institute and HospitalJi-Yeoun Lee - Seoul National University Children's HospitalTeiji Tominaga - Tohoku UniversityWilliam A Weiss - Neurological SurgeryJoanna J Phillips - University of California, San FranciscoShizhong Dai - University of California, San FranciscoGelareh Zadeh - Princess Margaret Cancer CentreAli G Saad - University of MiamiLászló Bognár - University of DebrecenAlmos Klekner - University of DebrecenIan F Pollack - University of PittsburghRonald L Hamilton - University of PittsburghYoung-Shin Ra - University of UlsanWieslawa A Grajkowska - Department of Pathology, The Children's Memorial Health Institute, Warsaw, PolandMarta Perek-Polnik - Children's Memorial Health InstituteReid C Thompson - Vanderbilt University Medical CenterAnna M Kenney - Emory UniversityMichael K Cooper - Vanderbilt University Medical CenterStephen C Mack - St. Jude Children's Research HospitalNada Jabado - McGill UniversityMathieu Lupien - University of TorontoMarco Gallo - Baylor College of MedicineVijay Ramaswamy - Hospital for Sick ChildrenMario L Suva - Broad InstituteHiromichi Suzuki - Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, JapanKathleen J Millen - University of WashingtonL Frank Huang - Mayo ClinicPaul A Northcott - St. Jude Children's Research HospitalMichael D Taylor - Texas Children's Hospital
- Nature genetics
- SU2C-AACR-DT-19-15 / EIF | Stand Up To Cancer (SU2C) R01NS106155 / U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01CA255369 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) 1R01CA270785-01A1 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) SU2C-AACR-DT1113 / EIF | Stand Up To Cancer (SU2C)
- Miller School of Medicine; UMMG Department of Pathology
- English
- Journal article
- 39753768
- 991032518761502976