The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.
Kui Ming Chan,Dong Fang,Haiyun Gan,Rintaro Hashizume,Chuanhe Yu,Mark A. Schroeder,Nalin Gupta,Sabine Mueller,C. David James,Robert B. Jenkins,Jann N. Sarkaria,Zhiguo Zhang +11 more
TL;DR: Results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.
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Abstract: Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.
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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.
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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TL;DR: It is demonstrated that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors.
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