Human H3F3A (phospho T45) peptide

PurposeDiffuse midline glioma with histone H3 K27M mutation is a new entity described in the 2016 update of the World Health Organization Classification of Tumors of the Central Nervous System. The purpose of this study was to evaluate the clinical and imaging characteristics to predict the presence of H3 K27M mutation in spinal cord glioma using a machine learning-based classification model.MethodsA total of 41 spinal cord glioma patients consisting of 24 H3 K27M mutants and 17 wild types were enrolled in this retrospective study. A total of 17 clinical and radiological features were evaluated. The random forest (RF) model was trained with the clinical and radiological features to predict the presence of H3 K27M mutation. The diagnostic ability of the RF model was evaluated using receiver operating characteristic (ROC) analysis. Area under the ROC curves (AUC) was calculated.ResultsMR imaging features of spinal cord diffuse midline gliomas were heterogeneous. Hemorrhage was the only variable that was able to differentiate H3 K27M mutated tumors from wild-type tumors in univariate analysis (p=0.033). RF classifier yielded 0.632 classification AUC (95% CI, 0.456-0.808), 63.4% accuracy, 45.8% sensitivity, and 88.2% specificity.ConclusionOur findings indicate that clinical and radiological features are associated with H3 K27M mutation status in spinal cord glioma.

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.