Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma

  title={Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma},
  author={Jeremy A Schwartzentruber and Andrey Korshunov and Xiao-yang Liu and David T. W. Jones and Elke Pfaff and Karine Jacob and Dominik Sturm and Adam M. Fontebasso and Dong Anh Khuong Quang and Martje T{\"o}njes and Volker Hovestadt and S Albrecht and Marcel Kool and Andr{\'e} Nantel and Carolin Konermann and Anders M Lindroth and Natalie J{\"a}ger and Tobias Rausch and Marina V. Ryzhova and Jan O. Korbel and Thomas Hielscher and P{\'e}ter Hauser and Mikl{\'o}s Garami and Almos Klekner and L{\'a}szl{\'o} Bogn{\'a}r and Martin Ebinger and Martin U. Schuhmann and Wolfram Scheurlen and Arnulf Pekrun and Michael Christoph Fr{\"u}hwald and Wolfgang Roggendorf and C Kramm and Matthias D{\"u}rken and Jeffrey Atkinson and Pierre Lepage and Alexandre Montpetit and Magdalena Zakrzewska and Krzystof Zakrzewski and Pawel P. Liberski and Zhifeng Dong and Peter M. Siegel and Andreas E. Kulozik and Marc Zapatka and Abhijit Guha and David Malkin and J{\"o}rg Felsberg and Guido Reifenberger and Andreas von Deimling and Koichi Ichimura and Vincent Peter Collins and Hendrik Witt and Till Milde and Olaf Witt and Cindy H. Zhang and Pedro Castelo-Branco and Peter Lichter and Damien Faury and Uri Tabori and Christoph Plass and Jacek Majewski and Stefan M. Pfister and Nada Jabado},
Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. [] Key Method To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions…

Epigenetics: Histone modification at the gene level

Recurrent mutations in H3F3A, particularly in high-grade paediatric gliomas, are identified, indicating that chromatin might be disrupted at multiple levels and have pleiotropic effects on gene expression, as might be expected from disruptions to chromatin.

Cancer genomics: Histone modification at the gene level

Recurrent mutations in H3F3A, particularly in high-grade paediatric gliomas, are identified, indicating that chromatin might be disrupted at multiple levels and whether any tumour-promoting effects of these mutations involve the dysregulated expression of a few or many cancer genes is currently unknown.

Evaluation of a novel antibody to define histone 3.3 G34R mutant brain tumours

The generation and validation of highly specific antibodies for G34 mutations are described, adding to an extremely valuable portfolio of antibodies, not only for histopathologic detection of tumour-associated mutant histone sequences, but also facilitating the study of spatial/anatomical aspects of tumours formation and the identification of downstream targets and pathways in malignant glioma progression.

The expanding landscape of ‘oncohistone’ mutations in human cancers

The characterization of missense histone mutations that occur across several cancer types provides insight into the potential role of these mutations in altering chromatin structure and potentially contributing to tumour development.

Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN.

The mechanistic explanation for how the first histone gene mutation inhuman disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem-cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric GBM is provided.

Upregulation of MYCN Histone H 3 . 3 Mutations Drive Pediatric Glioblastoma through

It is shown that the cerebral hemisphere-specifi c G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3) of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal.

Study of hTERT and Histone 3 Mutations in Medulloblastoma

Hotspot activating mutations of the telomerase reverse transcriptase (hTERT) promoter region were recently described in several tumor types, and are associated with older patients, prone to recurrence and located in the right cerebellar hemisphere in medulloblastoma.

Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail

These studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.

The role of histone modifications and telomere alterations in the pathogenesis of diffuse gliomas in adults and children

A review of mutations affecting the histone code and telomere length highlighting their importance in prognosis and as targets for novel therapeutics in the treatment of diffuse gliomas is presented.

Therapeutic Targeting of Histone Modifications in Adult and Pediatric High-Grade Glioma

This review focuses on the epigenetic mechanisms propagating pediatric and adult HGGs, as well as summarizing the current advances in clinical trials using HDAC inhibitors.



DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors

Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis and a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors was found.

The Genetic Landscape of the Childhood Cancer Medulloblastoma

Key differences between the genetic landscapes of adult and childhood cancers are demonstrated, dysregulation of developmental pathways as an important mechanism underlying MBs is highlighted, and a role for a specific type of histone methylation in human tumorigenesis is identified.

Inhibition of succinate dehydrogenase dysregulates histone modification in mammalian cells

The results support the notion that loss of mitochondrial function alters epigenetic processes and might provide a signature methylation mark for paraganglioma.

ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells.

It is shown that RNAi-knockdown of ATRX induces a telomere-dysfunction phenotype and significantly reduces CBX5 enrichment at the telomeres, which suggests a novel function of AtRX, working in conjunction with H3.3 and CBX 5, as a key regulator of ES-cell telomer chromatin.

Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas.

This first, complete, high-resolution profiling of the tumor cell genome fills an important gap in studies on p GBM and guides the mapping of oncogenic networks unique to pGBM, identification of the related therapeutic predictors and targets, and development of more effective therapies.

ATRX ADD domain links an atypical histone methylation recognition mechanism to human mental-retardation syndrome.

The cocrystal structure of ADD(ATRX) bound to H3(1-15)K9me3 peptide reveals an atypical composite H3K 9me3-binding pocket, which is distinct from the conventional trimethyllysine-binding aromatic cage and is discovered a unique histone-recognition mechanism underlying the ATR-X etiology.

Differential chromatin marking of introns and expressed exons by H3K36me3

It is proposed that H3K36me3 exon marking in chromatin provides a dynamic link between transcription and splicing, and is found at lower levels in alternatively spliced exons, supporting a splicing-related marking mechanism.

Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease.

Integrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients.