Abstract
Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1478-0) contains supplementary material, which is available to authorized users.
Highlights
Introduction two histoneH3 proteins are distinct in terms of expression during the cell cycle, chaperones for incorporation in the nucleosomes, localisation on the genome and presumably physiological functions [23, 54]
We analysed a cohort of 62 diffuse intrinsic pontine glioma (DIPG) biopsy samples obtained at diagnosis for (1) histone H3 lysine 27 trimethylation (Fig. 1a) and (2) immunodetection of the mutated H3-K27M histone (Fig. 1b) by IHC, and correlated these data with the mutational status obtained by Sanger sequencing on corresponding biopsy core (Fig. 1c)
The low tumour infiltration of the assayed sample impeded the detection of the H3K27me3 loss, but H3-K27M-mutated allele could be detected on a distinct sample in two of them, indicating that the lack of IHC detection can result from heterogeneity of distinct tissue sections (Supplemental Figure S2a)
Summary
Introduction two histoneH3 proteins are distinct in terms of expression during the cell cycle, chaperones for incorporation in the nucleosomes, localisation on the genome and presumably physiological functions [23, 54]. We sought to elucidate if K27M mutations in the distinct histone H3 variants (i.e. HIST1H3B and H3F3A) were associated with a specific biology and performed comprehensive histological, radiological, transcriptome and CGH array (aCGH) analyses on an extended cohort of DIPG cases biopsied at diagnosis selected with stringent clinical, radiological and histological integrated criteria. High-grade gliomas are the most common paediatric malignant brain neoplasms and among them diffuse intrinsic pontine glioma (DIPG) is a leading cause of death from solid tumours in children, with no improvement in outcome in decades. Surgery is not offered due to the infiltrative nature of the neoplasm in a delicate brain structure, and biopsy was abandoned in favour of a clinical and radiological diagnosis only [1]. Imaging parameters, when limited to morphological alterations, have not been associated with survival either [26]
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