Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma
Barbara S. Paugh,Alberto Broniscer,Chunxu Qu,Claudia P. Miller,Junyuan Zhang,Ruth G. Tatevossian,James M. Olson,J. Russell Geyer,Susan N. Chi,Nasjla Saba da Silva,Arzu Onar-Thomas,Justin N. Baker,Amar J. Gajjar,David W. Ellison,Suzanne J. Baker +14 more
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Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.Abstract:
Purpose Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. Results Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase–Ras–phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirt...read more
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Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.
Dominik Sturm,Hendrik Witt,Hendrik Witt,Volker Hovestadt,Dong Anh Khuong-Quang,David T.W. Jones,Carolin Konermann,Elke Pfaff,Martje Tönjes,Martin Sill,Sebastian Bender,Marcel Kool,Marc Zapatka,Natalia Becker,Manuela Zucknick,Thomas Hielscher,Xiaoyang Liu,Adam M. Fontebasso,Marina Ryzhova,Steffen Albrecht,Karine Jacob,Marietta Wolter,Martin Ebinger,Martin U. Schuhmann,Timothy E. Van Meter,Michael C. Frühwald,Holger Hauch,Arnulf Pekrun,Bernhard Radlwimmer,Tim Niehues,Gregor Von Komorowski,Matthias Dürken,Andreas E. Kulozik,Jenny Madden,Andrew M. Donson,Nicholas K. Foreman,Rachid Drissi,Maryam Fouladi,Wolfram Scheurlen,Andreas von Deimling,Andreas von Deimling,Camelia M. Monoranu,Wolfgang Roggendorf,Christel Herold-Mende,Andreas Unterberg,Christof M. Kramm,Jörg Felsberg,Christian Hartmann,Benedikt Wiestler,Wolfgang Wick,Till Milde,Till Milde,Olaf Witt,Olaf Witt,Anders Lindroth,Jeremy Schwartzentruber,Damien Faury,Adam Fleming,Magdalena Zakrzewska,Pawel P. Liberski,Krzysztof Zakrzewski,Peter Hauser,Miklós Garami,Almos Klekner,László Bognár,Sorana Morrissy,Florence M.G. Cavalli,Michael D. Taylor,Peter van Sluis,Jan Koster,Rogier Versteeg,Richard Volckmann,Tom Mikkelsen,Kenneth Aldape,Guido Reifenberger,V. Peter Collins,Jacek Majewski,Andrey Korshunov,Peter Lichter,Christoph Plass,Nada Jabado,Stefan M. Pfister,Stefan M. Pfister +82 more
TL;DR: It is demonstrated that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup.
Journal ArticleDOI
Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas
Gang Wu,Alberto Broniscer,Troy A. McEachron,Charles Lu,Barbara S. Paugh,Jared Becksfort,Chunxu Qu,Li Ding,Robert Huether,Matthew Parker,Junyuan Zhang,Amar Gajjar,Michael A. Dyer,Charles G. Mullighan,Richard J. Gilbertson,Elaine R. Mardis,Richard K. Wilson,James R. Downing,David W. Ellison,Jinghui Zhang,Suzanne J. Baker +20 more
TL;DR: To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPG and 36 non-brainstem pediatric glioblastomas (non-BS-PGs) were performed.
Journal ArticleDOI
The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma
Gang Wu,Alexander K. Diaz,Alexander K. Diaz,Barbara S. Paugh,Sherri Rankin,Bensheng Ju,Yongjin Li,Xiaoyan Zhu,Chunxu Qu,Xiang Chen,Junyuan Zhang,John Easton,Michael N. Edmonson,Xiaotu Ma,Charles Lu,Panduka Nagahawatte,Erin Hedlund,Michael Rusch,Stanley Pounds,Tong Lin,Arzu Onar-Thomas,Robert Huether,Richard W. Kriwacki,Matthew Parker,Pankaj Gupta,Jared Becksfort,Lei Wei,Heather L. Mulder,Kristy Boggs,Bhavin Vadodaria,Donald Yergeau,Jake C. Russell,Kerri Ochoa,Robert S. Fulton,Lucinda Fulton,Chris Jones,Frederick A. Boop,Alberto Broniscer,Cynthia Wetmore,Amar Gajjar,Li Ding,Elaine R. Mardis,Richard K. Wilson,Michael R. Taylor,James R. Downing,David W. Ellison,Jinghui Zhang,Suzanne J. Baker,Suzanne J. Baker +48 more
TL;DR: In this article, the authors analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGG (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing.
Journal ArticleDOI
K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.
Dong Anh Khuong-Quang,Pawel Buczkowicz,Patricia Rakopoulos,Xiaoyang Liu,Adam M. Fontebasso,Eric Bouffet,Ute Bartels,Steffen Albrecht,Jeremy Schwartzentruber,Louis Letourneau,Mathieu Bourgey,Guillaume Bourque,Alexandre Montpetit,Geneviève Bourret,Pierre Lepage,Adam Fleming,Peter Lichter,Marcel Kool,Andreas von Deimling,Dominik Sturm,Andrey Korshunov,Damien Faury,David T.W. Jones,Jacek Majewski,Stefan M. Pfister,Stefan M. Pfister,Nada Jabado,Nada Jabado,Cynthia Hawkins +28 more
TL;DR: Findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG, while patients wild-type for H2.3 show improved survival.
Journal ArticleDOI
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma
Alan Mackay,Anna Burford,Diana Carvalho,Elisa Izquierdo,Janat Fazal-Salom,Kathryn R. Taylor,Kathryn R. Taylor,Lynn Bjerke,Matthew Clarke,Mara Vinci,Meera Nandhabalan,Sara Temelso,Sergey Popov,Sergey Popov,Valeria Molinari,Pichai Raman,Angela J. Waanders,Harry J. Han,Saumya Gupta,Lynley V. Marshall,Stergios Zacharoulis,Sucheta Vaidya,Henry Mandeville,Leslie R. Bridges,Andrew J. Martin,Safa Al-Sarraj,Christopher Chandler,Ho Keung Ng,Xingang Li,Kun Mu,Saoussen Trabelsi,Dorra H'mida-Ben Brahim,Alexei N. Kisljakov,Dmitry M. Konovalov,Andrew S. Moore,Angel M. Carcaboso,Mariona Suñol,Carmen Torres,Ofelia Cruz,Jaume Mora,Ludmila I. Shats,João Norberto Stávale,Lucas Tadeu Bidinotto,Rui Manuel Reis,Natacha Entz-Werle,Michael A. Farrell,Jane Cryan,Darach Crimmins,John Caird,Jane Pears,Michelle Monje,Marie-Anne Debily,David Castel,Jacques Grill,Cynthia Hawkins,Hamid Nikbakht,Nada Jabado,Suzanne J. Baker,Stefan M. Pfister,Stefan M. Pfister,David T.W. Jones,Maryam Fouladi,André O. von Bueren,André O. von Bueren,Michael Baudis,Adam C. Resnick,Chris Jones +66 more
TL;DR: Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct, and co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H 3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H2.1K 27M are identified.
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Journal ArticleDOI
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