Hotspot Mutations in H3F3A and IDH1 Define Distinct Epigenetic and Biological Subgroups of Glioblastoma

Abstract

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show 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. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.

Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019

“…Mutation analysis by direct-sequencing and multiplex ligation-dependent probe amplification demonstrated in both 239/12 and 170/OG loss of function mutations in the TP53 tumor suppressor gene. Molecular characterization according to Sturm et al 7 was performed on all the ten cell lines. All the cells were screened for IDH1 mutations, as previously described, 8 TP53 mutation (all exons) and for H3F3A (first coding exon) using direct sequencing.…”

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

“…47,48 Applied genomewide DNA methylation profiling in cohorts of pediatric and adult patients also described recurrent age-specific mutations in H3F3A, while tumors enriched for PDGFRA alterations occur in patients from a wider age range. 29 These techniques also led to subgrouping DIPG patients based on CpG island methylation, identifying a subgroup with high-level amplification of MYCN and high-grade histology, in which targeting histones would be irrelevant. 31 Observations of DNA methylation profiles across all tumor sites in DIPG tissues was strongly associated with alterations in a specific histone 3 variant mark.…”

“…Historically, pediatric highgrade glioma was considered similar to secondary glioblastoma multiform (GBM), an adult high-grade glioma that evolves from a less malignant precursor due to changes in gene expression, such as OLIG1 and OLIG2, important neuro-developmental genes. 29 K27M mutations in histone H3.1 or H3. 3 In contrast to adult tumors, pediatric high-grade gliomas commonly have somatic oncogenic gene mutations (H3F3A and HIST1H3B), resulting in replacement of lysine 27 by methionine (K27M) in the encoded histone H3 proteins (Table 1).…”

Characterization of aberrant pathways across human cancers

“…These data have been used to identify clinically meaningful subtypes based on genomic and transcriptomic [9-16] or epigenomic profiles [17,18]. The standard approach of clustering samples based on only one type of data has recently been extended towards integration of multiple data types [19,20].…”