Genetic mutations in high grade gliomas of the adult spinal cord

Nagaishi, Masaya; Nobusawa, Sumihito; Yokoo, Hideaki; Sugiura, Yoshiki; Tsuda, Kyoji; Tanaka, Yoshihiro; Suzuki, Kensuke; Hyodo, Akio

doi:10.1007/s10014-016-0263-7

Cited by 27 publications

(22 citation statements)

References 9 publications

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“…Direct DNA sequencing for BRAF, IDH1/2, H3F3A, TP53 and TERT promoter mutations Genomic DNA extracted from FFPE sections was amplified and sequenced using the primers described previously (2,12,26,31,36,37). PCR products were sequenced on a 3130xl Genetic Analyzer (Applied Biosystems, Foster City, CA, USA) with the Big Dye Terminator v.1.1 Cycle Sequencing Kit (Applied Biosystems) following standard procedures.…”

Section: Array Comparative Genomic Hybridizationmentioning

confidence: 99%

BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity

et al. 2017

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Epithelioid glioblastoma (E-GBM) is a rare aggressive variant of IDH-wildtype glioblastoma newly recognized in the 2016 World Health Organization classification, composed predominantly of monotonous, patternless sheets of round cells with laterally positioned nuclei and plump eosinophilic cytoplasm. Approximately 50% of E-GBM harbor BRAF V600E, which is much less frequently found in other types of glioblastomas. Most E-GBM are recognized as primary/de novo lesions; however, several E-GBM with co- or pre-existing lower-grade lesions have been reported. To better understand associations between E-GBM and the lower-grade lesions, we undertook a histological and molecular analysis of 14 E-GBM, 10 of which exhibited lower-grade glioma-like components (8 E-GBM with co-existing diffuse glioma-like components, 1 E-GBM with a co-existing PXA-like component and 1 E-GBM with a pre-existing PXA). Molecular results demonstrated that the prevalence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions in E-GBM were 13/14 (93%), 10/14 (71%) and 11/14 (79%), respectively, and concurrent BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions were observed in 7/14 (50%) of E-GBM. These alterations were also frequently seen in the lower-grade lesions irrespective of the histology. Genetic analysis including array comparative genomic hybridization performed for 5 E-GBM with co- and pre-existing lower-grade components revealed that all molecular changes found in the lower-grade components were also observed in the E-GBM components, and additional changes were detected in the E-GBM components. In conclusion, E-GBM frequently exhibit BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions and these alterations tend to coexist in E-GBM. Taken together with the facts that only one PXA preceded E-GBM among these lower-grade lesions, and that co-occurrence of BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions have been reported to be rare in conventional lower-grade diffuse gliomas, the diffuse glioma-like components may be distinct infiltrative components of E-GBM, reflecting intratumoral heterogeneity.

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Section: Array Comparative Genomic Hybridizationmentioning

confidence: 99%

BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity

et al. 2017

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“…Nevertheless, even if the histological grade can be challenging to assess in the spine [32,41], it remains the most powerful prognostic marker [21,52], with LG IMAs associated with better outcomes than HG IMAs [11,21,55]. Our study showed that the tumor grade was associated with better OS, while EFS was strongly impacted by tumor grade and surgery, with a higher rate of disease progression in cases in which only biopsy could be performed.…”

Section: Discussionmentioning

confidence: 65%

Clinical, radiological and molecular characterization of intramedullary astrocytomas

Lebrun¹,

Meléndez²,

Blanchard³

et al. 2020

acta neuropathol commun

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Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Noncanonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.

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“…All of the reported spinal cord gliomas harboring BRAF V600E mutations are LGGs (Table ) . Among the 24 cases of spinal cord HGGs investigated, none of them harbored BRAF V600E mutation (Table ) . Hence, our case is the first report of a spinal cord HGG harboring BRAF V600E mutation.…”

Section: Discussionmentioning

confidence: 74%

Spinal cord anaplastic astrocytoma with BRAF V600E mutation: A case report and review of literature

et al. 2020

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A 17‐year‐old female complained of lower extremity pain that progressed to low back pain accompanied by paraparesis. Magnetic resonance imaging revealed a mass in the conus medullaris of the spinal cord at the thoracic spine 11–12 level. The patient underwent resection of the mass. The pathological diagnosis was anaplastic astrocytoma based on the densely proliferating astrocytic tumor cells without necrosis or microvascular proliferation. The patient received chemoradiotherapy with oral temozolomide and a total of 54 Gy of local irradiation, followed by 24 courses of temozolomide as maintenance chemotherapy. The patient survived for 8 years without tumor recurrence following the initial treatment. Genetic analysis of the tumor revealed a BRAF V600E mutation that has not yet been reported in spinal cord high‐grade gliomas (HGGs). In recent years, the molecular therapy targeting the BRAF V600E mutation has been applied in clinical practice for several cancer types. Although the frequency in spinal cord HGGs is uncertain, it is necessary to investigate BRAF V600E mutation as a potential therapeutic target in the future.

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Genetic mutations in high grade gliomas of the adult spinal cord

Cited by 27 publications

References 9 publications

BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity

BRAF V600E, TERT promoter mutations and CDKN2A/B homozygous deletions are frequent in epithelioid glioblastomas: a histological and molecular analysis focusing on intratumoral heterogeneity

Clinical, radiological and molecular characterization of intramedullary astrocytomas

Spinal cord anaplastic astrocytoma with BRAF V600E mutation: A case report and review of literature

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