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The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation.

ABSTRACT: Due to the rare incidence of spinal cord astrocytomas, their molecular features remain unclear. Here, we characterized the landscapes of mutations in H3 K27M, isocitrate dehydrogenase 1 (IDH1) R132H, BRAF V600E, and the TERT promoter in 83 diffuse spinal cord astrocytic tumors. Among these samples, thirty-five patients had the H3 K27M mutation; this mutant could be observed in histological grade II (40%), III (40%), and IV (20%) astrocytomas. IDH1 mutations were absent in 58 of 58 cases tested. The BRAF V600E mutation (7/57) was only observed in H3-wildtype astrocytomas, and was associated with a better prognosis in all histological grade II/III astrocytomas. TERT promoter mutations were observed in both H3 K27M-mutant (4/25) and -wildtype (9/33) astrocytomas, and were associated with a poor prognosis in H3-wildtype histological grade II/III astrocytomas. In the 2016 WHO classification of CNS tumors, H3 K27M-mutant diffuse midline gliomas, including spinal cord astrocytomas, are categorized as WHO grade IV. Here, we noticed that the median overall survival of histological grade II/III H3 K27M-mutant cases (n =?28) was significantly longer than that of either the total histological grade IV cases (n =?12) or the H3 K27M-mutant histological grade IV cases (n =?7). We also directly compared H3 K27M-mutant astrocytomas to H3-wildtype astrocytomas of the same histological grade. In histological grade II astrocytomas, compared to H3-wildtype cases (n?=?37), H3 K27M-mutant patients (n?=?14) had showed a significantly higher Ki-67-positive rate and poorer survival rate. However, no significant differences in these parameters were observed in histological grade III and IV astrocytoma patients. In conclusion, these findings indicate that spinal cord astrocytomas are considerably different from hemispheric and brainstem astrocytomas in terms of their molecular profiles, and that the histological grade cannot be ignored when assessing the prognosis of H3 K27M-mutant spinal cord astrocytomas.

SUBMITTER: Chai RC

PROVIDER: S-EPMC7106747 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation.

Chai Rui-Chao RC Zhang Yao-Wu YW Liu Yu-Qing YQ Chang Yu-Zhou YZ Pang Bo B Jiang Tao T Jia Wen-Qing WQ Wang Yong-Zhi YZ

Acta neuropathologica communications 20200330 1

Due to the rare incidence of spinal cord astrocytomas, their molecular features remain unclear. Here, we characterized the landscapes of mutations in H3 K27M, isocitrate dehydrogenase 1 (IDH1) R132H, BRAF V600E, and the TERT promoter in 83 diffuse spinal cord astrocytic tumors. Among these samples, thirty-five patients had the H3 K27M mutation; this mutant could be observed in histological grade II (40%), III (40%), and IV (20%) astrocytomas. IDH1 mutations were absent in 58 of 58 cases tested. ...[more]

PMID: 32228694

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Project description:H3 K27-altered diffuse midline glioma is a highly lethal pediatric-type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27-altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M-mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M-mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M-mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M-mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutations. The TP53-mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis <18 years old, p = 0.056). Cox regression and Kaplan-Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway, KRAS/PI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M-mutant spinal cord diffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.

Dataset Information

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation.

Publications

The molecular characteristics of spinal cord gliomas with or without H3 K27M mutation.

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