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Acta Neuropathologica
Published in: Acta Neuropathologica 5/2013

Open Access 01-05-2013 | Original Paper

Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas

Authors: Adam M. Fontebasso, Jeremy Schwartzentruber, Dong-Anh Khuong-Quang, Xiao-Yang Liu, Dominik Sturm, Andrey Korshunov, David T. W. Jones, Hendrik Witt, Marcel Kool, Steffen Albrecht, Adam Fleming, Djihad Hadjadj, Stephan Busche, Pierre Lepage, Alexandre Montpetit, Alfredo Staffa, Noha Gerges, Magdalena Zakrzewska, Krzystof Zakrzewski, Pawel P. Liberski, Peter Hauser, Miklos Garami, Almos Klekner, Laszlo Bognar, Gelareh Zadeh, Damien Faury, Stefan M. Pfister, Nada Jabado, Jacek Majewski

Published in: Acta Neuropathologica | Issue 5/2013

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Abstract

Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30 % of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15 % of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15 % of pediatric HGGs (11/73) and 8 % of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults.
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Metadata
Title
Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas
Authors
Adam M. Fontebasso
Jeremy Schwartzentruber
Dong-Anh Khuong-Quang
Xiao-Yang Liu
Dominik Sturm
Andrey Korshunov
David T. W. Jones
Hendrik Witt
Marcel Kool
Steffen Albrecht
Adam Fleming
Djihad Hadjadj
Stephan Busche
Pierre Lepage
Alexandre Montpetit
Alfredo Staffa
Noha Gerges
Magdalena Zakrzewska
Krzystof Zakrzewski
Pawel P. Liberski
Peter Hauser
Miklos Garami
Almos Klekner
Laszlo Bognar
Gelareh Zadeh
Damien Faury
Stefan M. Pfister
Nada Jabado
Jacek Majewski
Publication date
01-05-2013
Publisher
Springer-Verlag
Published in
Acta Neuropathologica / Issue 5/2013
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-013-1095-8

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