TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Marc, Remke, The Hospital for Sick Children; Vijay, Ramaswamy, The Hospital for Sick Children; John, Peacock, The Hospital for Sick Children; David J. H., Shih, The Hospital for Sick Children; Christian, Koelsche, University Hospital Heidelberg; Paul A., Northcott, German Cancer Research Center; Nadia, Hill, The Hospital for Sick Children; Florence M. G., Cavalli, The Hospital for Sick Children; Marcel, Kool, German Cancer Research Center; Xin, Wang, The Hospital for Sick Children; Stephen C., Mack, The Hospital for Sick Children; Mark, Barszczyk, The Hospital for Sick Children; A. Sorana, Morrissy, The Hospital for Sick Children; Xiaochong, Wu, The Hospital for Sick Children; Sameer, Agnihotri, The Hospital for Sick Children; Betty, Luu, The Hospital for Sick Children; David T.W., Jones, German Cancer Research Center (DKFZ); Livia, Garzia, The Hospital for Sick Children; Adrian M., Dubuc, The Hospital for Sick Children; Nataliya, Zhukova, The Hospital for Sick Children; Robert, Vanner, The Hospital for Sick Children; Johan M., Kros, Erasmus Medical Center; Pim J., French, Erasmus Medical Center; Erwin, Van Meir, Emory University; Rajeev, Vibhakar, University of Colorado; Karel, Zitterbart, Masaryk University; Jennifer A., Chan, University of Calgary; Laszlo, Bognar, University of Debrecen; Almos, Klekner, University of Debrecen; Boleslaw, Lach, McMaster University; Shin, Jung, Chonnam National University; Ali G., Saad, University of Arkansas; Linda M., Liau, David Geffen School of Medicine at UCLA; Steffen, Albrecht, McGill University; Massimo, Zollo, University of Naples; Michael, Cooper, Vanderbilt Medical Center; Reid C., Thompson, Vanderbilt Medical Center; Oliver O., Delattre, Institut Curie; Franck, Bourdeaut, Institut Curie; Francois F., Doz, Institut Curie; Miklos, Garami, Semmelweis University; Peter, Hauser, Semmelweis University; Carlos G., Carlotti, Universidade de São Paulo; Timothy E., Van Meter, Virginia Commonwealth University; Luca, Massimi, Catholic University Medical School; Daniel, Fults, University of Utah; Scott L., Pomeroy, Harvard Medical School; Toshiro, Kumabe, Tohoku University; Young Shin, Ra, University of Ulsan; Jeffrey R., Leonard, Washington University School of Medicine; Samer K., Elbabaa, Saint Louis University; Jaume, Mora, Hospital Sant Joan de Déu; Joshua B., Rubin, Washington University School of Medicine; Yoon-Jae, Cho, Stanford University; Roger E., McLendon, Duke University; Darrell D., Bigner, Duke University; Charles G., Eberhart, John Hopkins University; Maryam, Fouladi, University of Cincinnati; Robert J., Wechsler-Reya, Sanford-Burnham Medical Research Institute; Claudia C., Faria, The Hospital for Sick Children; Sidney E., Croul, University of Toronto; Annie, Huang, The Hospital for Sick Children; Eric, Bouffet, The Hospital for Sick Children; Cynthia E., Hawkins, The Hospital for Sick Children; Peter B., Dirks, The Hospital for Sick Children; William A., Weiss, University of California, San Francisco; Ulrich, Schuller, University of Munich; Ian F., Pollack, University of Pittsburgh; Stefan, Rutkowski, University Medical Center Hamburg-Eppendorf; David, Meyronet, University Lyon; Anne, Jouvet, University Lyon; Michelle, Fevre-Montange, University Lyon; Nada, Jabado, McGill University; Marta, Perek-Polnik, The Children’s Memorial Health Institute; Wieslawa A., Grajkowska, The Children’s Memorial Health Institute; Seung-Ki, Kim, Seoul National University Children’s Hospital; James T., Rutka, The Hospital for Sick Children; David, Malkin, The Hospital for Sick Children; Uri, Tabori, The Hospital for Sick Children; Stefan M., Pfister, German Cancer Research Center (DKFZ); Andrey, Korshunov, University Hospital Heidelberg; Andreas, von Deimling, University Hospital Heidelberg

Publication

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Persistent URL

https://open.library.emory.edu/purl/122v41nsbx-emory

Last modified

03/05/2025

Type of Material

Article

Authors

Marc Remke, The Hospital for Sick Children

Vijay Ramaswamy, The Hospital for Sick Children

John Peacock, The Hospital for Sick Children

David J. H. Shih, The Hospital for Sick Children

Christian Koelsche, University Hospital Heidelberg

Paul A. Northcott, German Cancer Research CenterNadia Hill, The Hospital for Sick ChildrenFlorence M. G. Cavalli, The Hospital for Sick ChildrenMarcel Kool, German Cancer Research CenterXin Wang, The Hospital for Sick ChildrenStephen C. Mack, The Hospital for Sick ChildrenMark Barszczyk, The Hospital for Sick ChildrenA. Sorana Morrissy, The Hospital for Sick ChildrenXiaochong Wu, The Hospital for Sick ChildrenSameer Agnihotri, The Hospital for Sick ChildrenBetty Luu, The Hospital for Sick ChildrenDavid T.W. Jones, German Cancer Research Center (DKFZ)Livia Garzia, The Hospital for Sick ChildrenAdrian M. Dubuc, The Hospital for Sick ChildrenNataliya Zhukova, The Hospital for Sick ChildrenRobert Vanner, The Hospital for Sick ChildrenJohan M. Kros, Erasmus Medical CenterPim J. French, Erasmus Medical CenterErwin Van Meir, Emory UniversityRajeev Vibhakar, University of ColoradoKarel Zitterbart, Masaryk UniversityJennifer A. Chan, University of CalgaryLaszlo Bognar, University of DebrecenAlmos Klekner, University of DebrecenBoleslaw Lach, McMaster UniversityShin Jung, Chonnam National UniversityAli G. Saad, University of ArkansasLinda M. Liau, David Geffen School of Medicine at UCLASteffen Albrecht, McGill UniversityMassimo Zollo, University of NaplesMichael Cooper, Vanderbilt Medical CenterReid C. Thompson, Vanderbilt Medical CenterOliver O. Delattre, Institut CurieFranck Bourdeaut, Institut CurieFrancois F. Doz, Institut CurieMiklos Garami, Semmelweis UniversityPeter Hauser, Semmelweis UniversityCarlos G. Carlotti, Universidade de São PauloTimothy E. Van Meter, Virginia Commonwealth UniversityLuca Massimi, Catholic University Medical SchoolDaniel Fults, University of UtahScott L. Pomeroy, Harvard Medical SchoolToshiro Kumabe, Tohoku UniversityYoung Shin Ra, University of UlsanJeffrey R. Leonard, Washington University School of MedicineSamer K. Elbabaa, Saint Louis UniversityJaume Mora, Hospital Sant Joan de DéuJoshua B. Rubin, Washington University School of MedicineYoon-Jae Cho, Stanford UniversityRoger E. McLendon, Duke UniversityDarrell D. Bigner, Duke UniversityCharles G. Eberhart, John Hopkins UniversityMaryam Fouladi, University of CincinnatiRobert J. Wechsler-Reya, Sanford-Burnham Medical Research InstituteClaudia C. Faria, The Hospital for Sick ChildrenSidney E. Croul, University of TorontoAnnie Huang, The Hospital for Sick ChildrenEric Bouffet, The Hospital for Sick ChildrenCynthia E. Hawkins, The Hospital for Sick ChildrenPeter B. Dirks, The Hospital for Sick ChildrenWilliam A. Weiss, University of California, San FranciscoUlrich Schuller, University of MunichIan F. Pollack, University of PittsburghStefan Rutkowski, University Medical Center Hamburg-EppendorfDavid Meyronet, University LyonAnne Jouvet, University LyonMichelle Fevre-Montange, University LyonNada Jabado, McGill UniversityMarta Perek-Polnik, The Children’s Memorial Health InstituteWieslawa A. Grajkowska, The Children’s Memorial Health InstituteSeung-Ki Kim, Seoul National University Children’s HospitalJames T. Rutka, The Hospital for Sick ChildrenDavid Malkin, The Hospital for Sick ChildrenUri Tabori, The Hospital for Sick ChildrenStefan M. Pfister, German Cancer Research Center (DKFZ)Andrey Korshunov, University Hospital HeidelbergAndreas von Deimling, University Hospital Heidelberg

Language

English

Date

2013-10-31

Publisher

Springer Verlag (Germany)

Publication Version

Final Published Version

Copyright Statement

License

Creative Commons Attribution 4.0 International

Final Published Version (URL)

http://dx.doi.org/10.1007/s00401-013-1198-2

Title of Journal or Parent Work

Acta Neuropathologica

ISSN

0001-6322

Volume

Issue

Start Page

End Page

Grant/Funding Information

MDT is supported by a CIHR Clinician Scientist Phase II award, funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and the University of Toronto, and operating funds from the Canadian Institutes of Health Research, the National Institutes of Health (R01CA159859 and R01CA148699) and the Pediatric Brain Tumor Foundation.
KZ acknowledges research support from MH CZ-DRO FNBr 65269705.
MR is supported by a fellowship from the Dr. Mildred Scheel Foundation for Cancer Research/German Cancer Aid and funds from the Baden-Wurttemberg Foundation.
VR is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship.
The authors declare no conflicts of interest.
AK was supported by the TAMOP-4.2.2A-11/1/KONV-2012-0025 project and the János Bolyai Scholarship of the Hungarian Academy of Sciences.

Supplemental Material (URL)

Abstract

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in < 5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Author Notes

Correspondence: Andreas von Deimling, Phone: +49-6221-564651, Fax: +49-6221-564566, Email: andreas.vondeimling@med.uni-heidelberg.de; Michael D. Taylor, Phone: +416-813-6427, Fax: +416-813-4975, Email: mdtaylor@sickkids.ca

Keywords

Research Categories

Health Sciences, Pathology
Biology, Neuroscience

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TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

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