The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults

Feng, Jie; Hao, Shuyu; Pan, Changcun; Wang, Yu; Wu, Zhen; Zhang, Junting; Yan, Hai; Zhang, Liwei; Wan, Hong

doi:10.1016/j.humpath.2015.07.002

Cited by 95 publications

(81 citation statements)

References 25 publications

(35 reference statements)

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“…This result coincides with our previous work in DIPG [5, 20], where we found H3K27M to be a negative prognostic marker in DIPG, albeit independent of tumour histology. Previous research investigating the impact of H3K27M on high grade adult midline tumours found a correlation between H3K27M and poor survival in the brainstem, but not the thalamus [1, 13]. Similar to this study, in our cohort high grade histology was associated with a poor outcome in both H3K27M and H3WT patients.…”

Section: Discussionsupporting

confidence: 87%

Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Ryall

Krishnatry

Arnoldo

et al. 2016

acta neuropathol commun

102

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Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0.63–17.55) and median survival was 6.43 (range, 0.01–27.63) years. Our cohort contained 42 and 22 tumours reviewed as low and high grade gliomas, respectively. Five (12 %) low grade and 11 (50 %) high grade gliomas were positive for the H3F3A/HIST1H3B K27M (H3K27M) mutation. Kaplan-Meier survival analysis revealed significantly worse overall survival for patients harbouring the H3K27M mutation versus H3F3A/HIST1H3B wild type (H3WT) samples (log-rank p < 0.0001) with a median survival of 1.02 vs. 9.12 years. Mitogen-activated protein kinase (MAPK) pathway activation via BRAF or FGFR1 hotspot mutations or fusion events were detected in 44 % of patients, and was associated with long-term survival in the absence of H3K27M (log-rank p < 0.0001). Multivariate analysis demonstrated H3K27M status and high grade histology to be the most significant independent predictors of poor overall survival with hazard ratios of 6.945 and 7.721 (p < 0.0001), respectively. In contrast, MAPK pathway activation is a predictor of favourable patient outcome, although not independent of other clinical factors. Importantly, we show that low grade malignancies may harbour H3K27M mutations and that these tumours show a dismal survival compared to low grade H3WT cases. Our data strongly supports the inclusion of targeted genetic testing in childhood thalamic tumours to most accurately stratify patients into appropriate risk groups.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0353-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 87%

Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Ryall

Krishnatry

Arnoldo

et al. 2016

acta neuropathol commun

102

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“…However, both our cases exhibited overexpression of FOXG1 and Olig2 in a manner Among several studies investigating diffuse astrocytoma, NOS of the spinal cord, only one of nine cases (11 %) exhibited H3F3A K27 M mutation [10]. Although we have no outcome data for spinal diffuse midline glioma, H3 K27 M-mutant, a previous study showed that diffuse midline glioma, H3 K27M mutant in brain stem and thalamus tended to be associated with poorer outcomes [8]. Collectively, these data propose the hypothesis that HGG of spinal cord with H3F3A K27M mutation may denote clinically primary glioblastomas, while cases without mutation are more likely to represent secondary glioblastomas.…”

contrasting

confidence: 50%

“…In contrast to intracranial diffuse gliomas, spinal diffuse gliomas commonly exhibit p53 mutation without IDH1/2 mutation. The mutation of IDH1 is also rare in other diffuse midline glioma but often seen in gliomas of the adult brainstem [7,8].…”

mentioning

confidence: 99%

Genetic mutations in high grade gliomas of the adult spinal cord

et al. 2016

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“…Multiple large studies have corroborated this finding [34],[35]. This is in contrast to K27M+ gliomas located in the thalamus of adult patients, where histone H3 status does not uniformly appear to portend worse prognosis [26],[32]. …”

Section: Histologic Classifications and Molecular Refinementsmentioning

confidence: 75%

“…Alternatively, these biopsies may have occurred early within the course of tumor progression before development of any high-grade histologic features. With the exception of a couple rare case reports of children with K27M+ gliomas with indolent behavior [32],[33], the vast majority of K27M+ gliomas in children have aggressive clinical course regardless of the grade of histologic features observed in biopsy specimens. Multiple large studies have corroborated this finding [34],[35].…”

Section: Histologic Classifications and Molecular Refinementsmentioning

confidence: 99%

Exploiting Molecular Biology for Diagnosis and Targeted Management of Pediatric Low-Grade Gliomas

2016

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The majority of brain tumors arising in children are low-grade gliomas. Although historically categorized together as pediatric low-grade gliomas, there is significant histologic and genetic diversity within this group. In general, prognosis for pediatric low-grade gliomas is excellent, and limitation of sequelae from tumor and treatment is paramount. Advances in high-throughput genetic sequencing and gene expression profiling are fundamentally changing the way pediatric low-grade gliomas are classified and managed. Here we review the histologic subtypes and highlight how recent advances in elucidating the molecular pathogenesis of these tumors have refined diagnosis and prognostication. Additionally, we discuss how characterizing specific genetic alterations has paved the way for the rational use of targeted therapies that are currently in various phase clinical trials.

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The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults

Cited by 95 publications

References 25 publications

Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma

Genetic mutations in high grade gliomas of the adult spinal cord

Exploiting Molecular Biology for Diagnosis and Targeted Management of Pediatric Low-Grade Gliomas

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