Intramedullary gangliogliomas: histopathologic and molecular features of 25 cases

Gessi, Marco; Dörner, Evelyn; Dreschmann, Verena; Antonelli, Manila; Waha, Andreas; Giangaspero, Felice; Gnekow, Astrid; Pietsch, Torsten

doi:10.1016/j.humpath.2015.09.041

Cited by 28 publications

(11 citation statements)

References 20 publications

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“… 18 To date, there are few studies specifically addressing the presence of KIAA1549–BRAF fusions and BRAF V600E point mutations in low-grade spinal cord tumors. One study by Gessi et al 22 found that spinal gangliogliomas do not harbor the BRAF V600E mutation in high frequency. Another study by Wang et al 23 acknowledged that very little work has been done in regards to understanding the role of BRAF mutations in spinal cord tumors.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas

Grob

Nobre

Campbell

et al. 2020

Neuro-Oncology Advances

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Background The MAPK/ERK pathway is involved in cell growth and proliferation, and mutations in BRAF have made it an oncogene of interest in pediatric cancer. Previous studies found that BRAF mutations as well as KIAA1549-BRAF fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic changes in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG. Methods We retrospectively analyzed 46 spinal gliomas from patients age 1-25 years from Children’s Hospital Colorado (CHCO) and The Hospital for Sick Children (Sick Kids). CHCO utilized a 67 gene panel which assessed BRAF and additionally screened for other possible genetic abnormalities of interest. At Sick Kids, BRAFV600E was assessed by ddPCR and IHC. BRAF fusions were detected by FISH, RT-PCR or Nanostring platform. Data was correlated with clinical information. Results Of 31 samples with complete fusion analysis, 13 (42%) harbored KIAA1549-BRAF. All thirteen (100%) patients with confirmed KIAA1549-BRAF survived the entirety of the study period (median [interquartile range, IQR] follow-up time: 47 months [27-85 months]) and fifteen (83.3%) fusion negative patients survived (follow-up time: 37.5 (19.8-69.5 months). Other mutations of interest were also identified in this patient cohort including BRAFV600E, PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion. Conclusion KIAA1549-BRAF was seen in higher frequency than BRAFV600E or other genetic aberrations in pediatric spinal LGGs and experienced lower death rates compared to KIAA1549-BRAF negative patients, although this was not statistically significant.

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Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas

Grob

Nobre

Campbell

et al. 2020

Neuro-Oncology Advances

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“…The activating p.V600E hotspot mutation in the BRAF oncogene has been identified in a subset of gangliogliomas, ranging from approximately 10–60% depending on the study and anatomic site, with highest frequencies reported in cortical tumors and lower frequency reported in spinal cord tumors [ 6 , 7 , 9 , 11 – 13 , 16 , 21 , 27 , 30 , 31 , 36 – 38 ]. However, BRAF p.V600E mutation is not specific to ganglioglioma and has been described in a wide spectrum of neuroepithelial tumors including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNET), pediatric IDH-wildtype diffuse astrocytoma, polymorphous low-grade neuroepithelial tumor of the young (PLNTY), pleomorphic xanthoastrocytoma, and epithelioid glioblastoma [ 6 , 12 , 17 , 22 , 30 , 31 , 36 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

The genetic landscape of ganglioglioma

Pekmezci

Villanueva-Meyer

Goode

et al. 2018

acta neuropathol commun

135

129

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Ganglioglioma is the most common epilepsy-associated neoplasm that accounts for approximately 2% of all primary brain tumors. While a subset of gangliogliomas are known to harbor the activating p.V600E mutation in the BRAF oncogene, the genetic alterations responsible for the remainder are largely unknown, as is the spectrum of any additional cooperating gene mutations or copy number alterations. We performed targeted next-generation sequencing that provides comprehensive assessment of mutations, gene fusions, and copy number alterations on a cohort of 40 gangliogliomas. Thirty-six harbored mutations predicted to activate the MAP kinase signaling pathway, including 18 with BRAF p.V600E mutation, 5 with variant BRAF mutation (including 4 cases with novel in-frame insertions at p.R506 in the β3-αC loop of the kinase domain), 4 with BRAF fusion, 2 with KRAS mutation, 1 with RAF1 fusion, 1 with biallelic NF1 mutation, and 5 with FGFR1/2 alterations. Three gangliogliomas with BRAF p.V600E mutation had concurrent CDKN2A homozygous deletion and one additionally harbored a subclonal mutation in PTEN. Otherwise, no additional pathogenic mutations, fusions, amplifications, or deletions were identified in any of the other tumors. Amongst the 4 gangliogliomas without canonical MAP kinase pathway alterations identified, one epilepsy-associated tumor in the temporal lobe of a young child was found to harbor a novel ABL2-GAB2 gene fusion. The underlying genetic alterations did not show significant association with patient age or disease progression/recurrence in this cohort. Together, this study highlights that ganglioglioma is characterized by genetic alterations that activate the MAP kinase pathway, with only a small subset of cases that harbor additional pathogenic alterations such as CDKN2A deletion.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0551-z) contains supplementary material, which is available to authorized users.

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“…Grade I GG accounts for 1%–5% of all central nervous system neoplasms in children; most are found in the cortex, generally in the temporal lobe (>70%) . However, they can occur in the posterior fossa or spinal cord, and other midline locations have also been reported . GGs in the brainstem or spinal cord exhibit a poorer prognosis.…”

Section: Introductionmentioning

confidence: 99%

Co‐occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma

Pagès

Beccaria²,

Boddaert³

et al. 2017

Brain Pathology

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Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As cooccurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.

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Intramedullary gangliogliomas: histopathologic and molecular features of 25 cases

Cited by 28 publications

References 20 publications

Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas

Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas

The genetic landscape of ganglioglioma

Co‐occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma

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