Histone H3K27M Mutation Overrides Histological Grading in Pediatric Gliomas

Mosaab, Amal; El‐Ayadi, Moatasem; Khorshed, Eman; Amer, Nada; Refaat, Amal; El-Beltagy, Mohamed; Hassan, Zeinab; Soror, Sameh H.; Zaghloul, Mohamed S.; El‐Naggar, Shahenda

doi:10.1038/s41598-020-65272-x

Cited by 53 publications

(31 citation statements)

References 38 publications

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“… 8 , 9 Pediatric patients with H3 K27M-mutant DMGs have a poor prognosis, with a median overall survival (mOS) of 10–14 months, 10–14 hence the rationale for the 2016 WHO Classification of Tumors of the CNS to designate these tumors as grade IV tumors, irrespective of histologic features such as necrosis or microvascular proliferation. 15 Prognosis is less clear in adult DMG harboring the H3 K27M mutation 16 , 17 ; this may in part depend on differences in location and spatially regulated gene expression.…”

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confidence: 99%

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults

Schulte

Buerki

Lapointe

et al. 2020

Neuro-Oncology Advances

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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. Methods Patient 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 (PFS) and overall survival (OS) was conducted using Kaplan-Meier modeling, univariate, and multivariate analysis. Results Median 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 diffuse midline gliomas. 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. Conclusions Together, these findings indicate that H3 K27M-mutant diffuse midline glioma represents a heterogeneous disease with regards to outcomes, sites of origin, and molecular pathogenesis in adults versus children.

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confidence: 99%

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults

Schulte

Buerki

Lapointe

et al. 2020

Neuro-Oncology Advances

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“…Over the past few decades, patient survival remains unchanged despite recent advances in understanding their biology and genetic landscape. Based on their aggressiveness, diffuse midline gliomas can range from WHO grade II to IV, but they have always been considered grade IV clinically because of their universally poor prognosis 39,40 .…”

Section: Discussionmentioning

confidence: 99%

H3K27M-mutant Diffuse Midline Gliomas should be Further Molecularly Stratified: An Integrated Analysis of 669 Patients

Vuong

Ngo

et al. 2021

Preprint

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Introduction: H3K27M-mutated diffuse midline gliomas (H3-DMGs) are aggressive tumors with a fatal outcome. This study integrating individual patient data (IPD) from published studies aimed to investigate the prognostic impact of different genetic alterations on survival of these patients.Methods: We accessed PubMed and Web of Science to search for relevant articles. Studies were included if they have available data of follow-up and additional molecular investigation of H3-DMGs. For survival analysis, Kaplan-Meier analysis and Cox regression models were utilized, and corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of genetic events on overall survival (OS).Result: We included 30 studies with 669 H3-DMGs. TP53 mutations were the most common second alteration among these neoplasms. In univariate Cox regression model, TP53 mutation was an indicator of shortened survival (HR = 1.446; 95% CI = 1.143-1.829) whereas ACVR1 (HR = 0.712; 95% CI = 0.518-0.976) and FGFR1 mutations (HR = 0.408; 95% CI = 0.208-0.799) conferred prolonged survival. In addition, ATRX loss was also associated with a better OS (HR = 0.620; 95% CI = 0.386-0.996). Adjusted for age, gender, tumor location, and the extent of resection, the presence of TP53 mutations, the absence of ACVR1 or FGFR1 mutations remained significantly poor prognostic factors.Conclusions: We outlined the prognostic importance of additional genetic alterations in H3-DMGs and recommended that these neoplasms should be further molecularly segregated. It could help neuro-oncologists better evaluate the risk stratification of patients and consider pertinent treatments.

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“…Much like IDH1/2 mutations, improved understanding of epigenetic dysregulation in glioma has led to the discovery of mutations encoding a lysine to methionine substitution at position 27 in histone H3 (H3K27M), which leads to the formation of high-grade gliomas, especially diffuse midline gliomas in children [ 175 , 176 , 177 ]. The introduction of newly identified mutations into murine models of glioma is expected to open new avenues for preclinical investigation of novel glioma onco-genotypes in future studies.…”

Section: Special Consideration For Idh1/2 Mutationsmentioning

confidence: 99%

Contemporary Mouse Models in Glioma Research

Hicks

Bird

Traylor

et al. 2021

Cells

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Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.

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Histone H3K27M Mutation Overrides Histological Grading in Pediatric Gliomas

Cited by 53 publications

References 38 publications

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults

H3K27M-mutant Diffuse Midline Gliomas should be Further Molecularly Stratified: An Integrated Analysis of 669 Patients

Contemporary Mouse Models in Glioma Research

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