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

Abstract

Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. 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 within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.

Surveying the epigenomic landscape, one base at a time

“…Additionally, hundreds of chromatin-associated proteins, including ATP-dependent chromatin remodelers [6] and histone modifying enzymes [5], interact with chromatin to modulate its structure. Notably, mutations in nucleosome remodelers and in the histone constituents of chromatin have been implicated in human developmental disorders and cancer [6,7]. Thus, high-resolution genomic analysis of chromatin structure and the proteins that influence it is a major focus of biological technology development to study both basic cellular processes and the pathogenesis of human disease.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…For example, glycine 34 to tryptophan/leucine (G34W/L) mutations occur in giant cell tumors of the bone, lysine 36 to methionine (K36M) mutations have been reported in »95% of chondroblastomas, and H3K36 mutations promote sarcomagenesis. [39][40][41][42] Associated changes in DNA methylation patterns DNA methylation patterns have been extensively studied in adult GBM and have helped guide clinical trials, predicting the recurrence of tumors and resistance to radiotherapy. Indeed, CpG island methylator phenotype (G-CIMP) helped subdivide GBMs into glioma, G-CIMP-positive and G-CIMP-negative GBM subsets, partially predicting response to treatment.…”

An Incidental Diffuse Midline Glioma Found at Autopsy

“…Tumor also 1 University of Florida -Pathology, Gainesville, FL. 2 extended into the tegmentum of the medulla and the inferior olives.…”

“…They are also likely to be widely infiltrative and nonresectable, although these tumors are not known to metastasize outside of the central nervous system. The overall 2-year survival is around 20% for these malignant pediatric tumors (2).…”