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Open Access 01-12-2013 | Original Paper

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Authors: Marc Remke, Vijay Ramaswamy, John Peacock, David J. H. Shih, Christian Koelsche, Paul A. Northcott, Nadia Hill, Florence M. G. Cavalli, Marcel Kool, Xin Wang, Stephen C. Mack, Mark Barszczyk, A. Sorana Morrissy, Xiaochong Wu, Sameer Agnihotri, Betty Luu, David T. W. Jones, Livia Garzia, Adrian M. Dubuc, Nataliya Zhukova, Robert Vanner, Johan M. Kros, Pim J. French, Erwin G. Van Meir, Rajeev Vibhakar, Karel Zitterbart, Jennifer A. Chan, László Bognár, Almos Klekner, Boleslaw Lach, Shin Jung, Ali G. Saad, Linda M. Liau, Steffen Albrecht, Massimo Zollo, Michael K. Cooper, Reid C. Thompson, Oliver O. Delattre, Franck Bourdeaut, François F. Doz, Miklós Garami, Peter Hauser, Carlos G. Carlotti, Timothy E. Van Meter, Luca Massimi, Daniel Fults, Scott L. Pomeroy, Toshiro Kumabe, Young Shin Ra, Jeffrey R. Leonard, Samer K. Elbabaa, Jaume Mora, Joshua B. Rubin, Yoon-Jae Cho, Roger E. McLendon, Darell D. Bigner, Charles G. Eberhart, Maryam Fouladi, Robert J. Wechsler-Reya, Claudia C. Faria, Sidney E. Croul, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, Peter B. Dirks, William A. Weiss, Ulrich Schüller, Ian F. Pollack, Stefan Rutkowski, David Meyronet, Anne Jouvet, Michelle Fèvre-Montange, Nada Jabado, Marta Perek-Polnik, Wieslawa A. Grajkowska, Seung-Ki Kim, James T. Rutka, David Malkin, Uri Tabori, Stefan M. Pfister, Andrey Korshunov, Andreas von Deimling, Michael D. Taylor

Published in: Acta Neuropathologica | Issue 6/2013

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.

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Title: TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma
Authors: Marc Remke
Vijay Ramaswamy
John Peacock
David J. H. Shih
Christian Koelsche
Paul A. Northcott
Nadia Hill
Florence M. G. Cavalli
Marcel Kool
Xin Wang
Stephen C. Mack
Mark Barszczyk
A. Sorana Morrissy
Xiaochong Wu
Sameer Agnihotri
Betty Luu
David T. W. Jones
Livia Garzia
Adrian M. Dubuc
Nataliya Zhukova
Robert Vanner
Johan M. Kros
Pim J. French
Erwin G. Van Meir
Rajeev Vibhakar
Karel Zitterbart
Jennifer A. Chan
László Bognár
Almos Klekner
Boleslaw Lach
Shin Jung
Ali G. Saad
Linda M. Liau
Steffen Albrecht
Massimo Zollo
Michael K. Cooper
Reid C. Thompson
Oliver O. Delattre
Franck Bourdeaut
François F. Doz
Miklós Garami
Peter Hauser
Carlos G. Carlotti
Timothy E. Van Meter
Luca Massimi
Daniel Fults
Scott L. Pomeroy
Toshiro Kumabe
Young Shin Ra
Jeffrey R. Leonard
Samer K. Elbabaa
Jaume Mora
Joshua B. Rubin
Yoon-Jae Cho
Roger E. McLendon
Darell D. Bigner
Charles G. Eberhart
Maryam Fouladi
Robert J. Wechsler-Reya
Claudia C. Faria
Sidney E. Croul
Annie Huang
Eric Bouffet
Cynthia E. Hawkins
Peter B. Dirks
William A. Weiss
Ulrich Schüller
Ian F. Pollack
Stefan Rutkowski
David Meyronet
Anne Jouvet
Michelle Fèvre-Montange
Nada Jabado
Marta Perek-Polnik
Wieslawa A. Grajkowska
Seung-Ki Kim
James T. Rutka
David Malkin
Uri Tabori
Stefan M. Pfister
Andrey Korshunov
Andreas von Deimling
Michael D. Taylor
Publication date: 01-12-2013
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 6/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-013-1198-2

At a glance: The STEP trials

Springer Medicine

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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Other articles of this Issue 6/2013

Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins

C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci

Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS

Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations

TERT promoter mutations in primary and secondary glioblastomas

Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood