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 |
REPOSITORIES: biostudies-literature
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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:Mutations within FGFR1 and BRAF indicate superior outcome in diffuse midline gliomas, H3F3A K27M mutant
| PRJNA679958 | ENA
Project description:INTRODUCTION: Mutations 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. METHODS: Genomic 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. RESULTS: Of 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. CONCLUSION: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.
| S-EPMC3870821 | biostudies-other
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:Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10, and recent results suggest benefit in central nervous system malignancies11-13. Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2. Anti-GD2 CAR T cells incorporating a 4-1BBz costimulatory domain 14 demonstrated robust antigen-dependent cytokine generation and killing of DMG cells in vitro. In five independent patient-derived H3-K27M+ DMG orthotopic xenograft models, systemic administration of GD2-targeted CAR T cells cleared engrafted tumors except for a small number of residual GD2lo glioma cells. To date, GD2-targeted CAR T cells have been well tolerated in clinical trials15-17. Although GD2-targeted CAR T cell administration was tolerated in the majority of mice bearing orthotopic xenografts, peritumoral neuroinflammation during the acute phase of antitumor activity resulted in hydrocephalus that was lethal in a fraction of animals. Given the precarious neuroanatomical location of midline gliomas, careful monitoring and aggressive neurointensive care management will be required for human translation. With a cautious multidisciplinary clinical approach, GD2-targeted CAR T cell therapy for H3-K27M+ diffuse gliomas of pons, thalamus and spinal cord could prove transformative for these lethal childhood cancers.
| S-EPMC6214371 | 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
Project description:Background"Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.MethodsPatient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.ResultsMedian patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.ConclusionsTogether, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.
| S-EPMC7739048 | biostudies-literature
Project description:PURPOSE:H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation. METHODS:Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX. RESULTS:Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n?=?18; 17.6 months) compared with high-grade wildtype tumors (n?=?74; 7.7 months, p?=?0.03). CONCLUSIONS:H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.
| S-EPMC6482123 | biostudies-literature
Project description:Background:The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Methods:Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. Results:We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. Conclusion:These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.
| S-EPMC5761525 | biostudies-literature