Correction to: Mutations within FGFR1 are associated with superior outcome in a series of 83 diffuse midline gliomas with H3F3A K27M mutations.
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ABSTRACT:
SUBMITTER: Schuller U
PROVIDER: S-EPMC8182839 | biostudies-literature | 2021 Apr
REPOSITORIES: biostudies-literature
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Correction to: Mutations within FGFR1 are associated with superior outcome in a series of 83 diffuse midline gliomas with H3F3A K27M mutations.
Schüller Ulrich U Iglauer Peter P Dorostkar Mario M MM Mawrin Christian C Herms Jochen J Giese Armin A Glatzel Markus M Neumann Julia E JE
Acta neuropathologica 20210401 4
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Project description: Not available
| S-EPMC7847449 | biostudies-literature
Project description:Diffuse midline glioma (DMG) is a devastating disease that is defined by its localization, by the diffuse growth of astrocytic tumor cells, and by K27M mutations within Histone H3 proteins. In a large series of such tumor samples (n=83), we show here that 12 % of these cases (n=10) harbor concomitant hotspot mutations within FGFR1 or BRAF. Respective cases were all located in midline structures and matched with reference cases of DMG using global DNA methylation profiling. TP53 mutations were significantly more frequent in BRAF/FGFR1 wild type cases. Presence of hotspot mutations within FGFR1 or BRAF was associated with a significantly better overall survival, which was independent of the patients’ age and tumor localization. Thus, our results establish the relevance of FGFR1 or BRAF mutations in DMG as a prognostic marker and open new targeted therapy options in this subgroup of DMG.
2020-12-08 | GSE161944 | GEO
Project description: Not available
| S-EPMC6078201 | biostudies-literature
Project description:Mutations within FGFR1 and BRAF indicate superior outcome in diffuse midline gliomas, H3F3A K27M mutant
| PRJNA679958 | ENA
Project description:IntroductionMutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. Here, we sought to determine the association between H3F3A mutations and adult thalamic glioma.MethodsGenomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes--including cancer-related genes and chromatin-modifier genes--were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome.ResultsOf the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 y; range, 17-46), and 7 were from patients over 50 years of age. The H3F3A K27M mutation was present in 10 of the 11 (91%) younger patients and absent from all 7 older patients. Additionally, H3F3A K27M was not detected in the 2 diffuse astrocytomas. Further sequencing revealed recurrent mutations in TP53, ATRX, NF1, and EGFR. Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas.ConclusionWe found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.
| S-EPMC3870821 | biostudies-literature
Project description: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.
| S-EPMC4654747 | biostudies-literature
Project description:Diffuse midline glioma, H3 K27M-mutant is a lethal brain tumor located in the thalamus, brain stem, or spinal cord. H3 K27M encoded by the mutation of a histone H3 gene such as H3F3A plays a pivotal role in the tumorigenesis of this type of glioma. Although several studies have revealed comprehensive genetic and epigenetic profiling, the prognostic factors of these tumors have not been identified to date. In various cancers, oncogenic driver genes have been found to exhibit characteristic copy number alterations termed mutant allele specific imbalance (MASI). Here, we showed that several diffuse midline glioma, H3 K27M-mutant exhibited high variant allele frequency (VAF) of the mutated H3F3A gene using droplet digital polymerase chain reaction (ddPCR) assays. Whole-genome sequencing (WGS) revealed that these cases had various copy number alterations that affected the mutant and/or wild-type alleles of the H3F3A gene. We also found that these MASI cases showed a significantly higher Ki-67 index and poorer survival compared with those in the lower VAF cases (P < 0.05). Our results indicated that the MASI of the H3F3A K27M mutation was associated with the aggressive phenotype of the diffuse midline glioma, H3 K27M-mutant via upregulation of the H3 K27M mutant protein, resulting in downregulation of H3K27me3 modification.
| S-EPMC7001313 | biostudies-literature
Project description:BackgroundH3K27M mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%. Radiotherapy is the only established adjuvant treatment of H3K27M DMGs; however, the radio-resistance is commonly observed.MethodsWe summarized current understandings of the molecular responses of H3K27M DMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement.ResultsIonizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial-mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio-resistance.ConclusionsThe advances in mechanisms of radio-resistance in H3K27M DMGs promote the potential targets to enhance the sensitivity to radiotherapy.
| S-EPMC10324372 | biostudies-literature
Project description:BackgroundConventional MR imaging has limited value in identifying H3 K27M mutations. We aimed to investigate the capacity of quantitative MR imaging variables in identifying the H3 K27M mutation status of diffuse midline glioma.Materials and methodsTwenty-three patients with H3 K27M mutation and thirty-two wild-type patients were recruited in this retrospective study, all of whom underwent multimodal MR imaging. Clinical data and quantitative MR imaging variables were explored by subgroup analysis stratified by age (juveniles and adults). Then, a logistic model for all patients was constructed to identify potential variables for predicting K27M mutation status. Besides, a retrospective validation set including 13 patients was recruited. The C-index and F1 score were used to evaluate the performance of the prediction model.ResultsIt turned out that patients with H3 K27M mutation were younger in the adult subgroup. In the mutation group, some relative apparent diffusion coefficient (rADC) histogram parameters and myo-inositol/creatine plus phosphocreatine (Ins/tCr) ratio were lower than in the wild-type group of both juveniles and adults (p < 0.05). After nested cross-validation and LASSO algorithm, the age, Ins/tCr, and rADC_15th were selected as potential predictors for H3 K27M mutation in the model. The nomogram model showed good diagnostic power with a validated C-index of 0.884. In addition, the area under the curve (AUC) was 0.898 (0.976 in validation set) and the F1 score was 0.732.ConclusionsIn conclusion, age, rADC_15th, and Ins/tCr values were helpful in identifying H3 K27M mutations in midline gliomas.
| S-EPMC8855915 | biostudies-literature
Project description:ObjectivesTo explore the magnetic resonance imaging (MRI) characteristics of brain diffuse midline gliomas with the H3 K27M mutation (DMG-M) using radiomics.Materials and methodsThirty patients with diffuse midline gliomas, including 16 with the H3 K27M mutant and 14 with wild type tumors, were retrospectively included in this study. A total of 272 radiomic features were initially extracted from MR images of each tumor. Principal component analysis, univariate analysis, and three other feature selection methods, including variance thresholding, recursive feature elimination, and the elastic net, were used to analyze the radiomic features. Based on the results, related visually accessible features of the tumors were further evaluated.ResultsPatients with DMG-M were younger than those with diffuse midline gliomas with H3 K27M wild (DMG-W) (median, 25.5 and 48 years old, respectively; p=0.005). Principal component analysis showed that there were obvious overlaps in the first two principal components for both DMG-M and DMG-W tumors. The feature selection results showed that few features from T2-weighted images (T2WI) were useful for differentiating DMG-M and DMG-W tumors. Thereafter, four visually accessible features related to T2WI were further extracted and analyzed. Among these features, only cystic formation showed a significant difference between the two types of tumors (OR=7.800, 95% CI 1.476-41.214, p=0.024).ConclusionsDMGs with and without the H3 K27M mutation shared similar MRI characteristics. T2W sequences may be valuable, and cystic formation a useful MRI biomarker, for diagnosing brain DMG-M.
| S-EPMC8182051 | biostudies-literature