Epithelioid GBMs Show a High Percentage of BRAF V600E Mutation

Kleinschmidt‐DeMasters, Bette K.; Aisner, Dara L.; Birks, Diane K.; Foreman, Nicholas K.

doi:10.1097/pas.0b013e31827f9c5e

Cited by 237 publications

(236 citation statements)

References 39 publications

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“…If the presence of BRAF‐V600E mutation is a diagnostic clue to a circumscribed low‐grade glial or glial–neuronal tumor, this mutation is not specific of GNT; it has been reported in rare cases of low‐grade diffuse gliomas in children and in 10% of GB, especially in the epithelioïd variant (which also expresses CD34 more often) (Brastianos et al., 2014; Ichimura et al., 2012; Kleinschmidt‐DeMasters, Aisner, & Foreman, 2015; Kleinschmidt‐DeMasters et al., 2013). The detection of the mutation can still help to distinguish a GG from the cortical infiltration of a diffuse glioma or a GG from an astrocytoma especially in the cerebellum, where PA rarely exhibits BRAF‐V600E mutation (but instead the BRAF‐KIAA1549 fusion in 80% of cases).…”

Section: Discussionmentioning

confidence: 99%

“…BRAF rearrangements have also been identified in CNS tumors (Brastianos et al., 2014; Dias‐Santagata et al., 2011; Dougherty et al., 2010; Kleinschmidt‐DeMasters, Aisner, Birks, & Foreman, 2013; Koelsche et al., 2013, 2014). Very recently, the mutation V600E has been reported in 96% of papillary craniopharyngiomas (Brastianos et al., 2014).…”

Section: Introductionmentioning

confidence: 99%

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BRAF‐V600E immunohistochemistry in a large series of glial and glial–neuronal tumors

et al. 2017

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IntroductionSome glial–neuronal tumors (GNT) (pleomorphic xantho‐astrocytoma [PXA], ganglioglioma [GG]) display BRAF‐V600E mutation, which represents a diagnostic clue to these entities. Targeted therapies against BRAF‐V600 protein have shown promising results in GNT. The aim of this study was to assess the utility of BRAF‐V600E immunohistochemistry (IHC, clone VE1) in daily practice in a series of 140 glial, and GNT compared to molecular biology (MB) techniques.MethodsWe performed BRAF‐V600E IHC on all 140 cases. We used Sanger sequencing and allele‐specific quantitative PCR (ASQ‐PCR) to detect BRAF‐V600E mutation when sufficient amount of materiel was available.Results BRAF‐V600E immunostaining was detected in 29.5% of cases (41/140 cases; 61.5% GG/GC/AGG (32/52), 33% PXA, 6.6% pilocytic astrocytomas). In 47 cases, MB could be performed: Sanger sequencing and ASQ‐PCR in 34 cases, ASQ‐PCR only in 11 cases, and Sanger sequencing only in two cases. In initial tumors, Sanger sequencing identified BRAF‐V600E mutation in 19.5% tumors (seven of 36 tested cases). ASQ‐PCR showed mutation in 48.5% tumors (17/35 tested cases). In six cases (5 GG, one PXA), the results were discordant between IHC and MB; the five GG cases were immunopositive for BRAF‐V600E but wild type with both MB techniques. In another 7 GG, the percentage of mutated (ganglion) cells was low, and Sanger sequencing failed to detect the mutation, which was detected by IHC and ASQ‐PCR.ConclusionsIn tumors with few mutated cells (e.g., GG), anti‐BRAF‐V600E IHC appears more sensitive than Sanger sequencing. The latter, although considered as the gold standard, is not to be used up‐front to detect BRAF mutation in GG. The combination of IHC and ASQ‐PCR appears more efficient to appraise the indication of targeted therapies in these glioneuronal tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BRAF‐V600E immunohistochemistry in a large series of glial and glial–neuronal tumors

et al. 2017

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“…It is characterized by relatively solid aggregates of large "melanoma-like" epithelioid cells with abundant eosinophilic cytoplasm, some eccentrically placed nuclei, prominent nucleoli and distinct cellular membranes (8,22,23). While one study makes a distinction between eGBM and rhabdoid GBM based on the focal loss of INI1 immunoreactivity in rhabdoid areas (9), there is considerable overlap and others use these terms interchangeably (11,17,27).…”

Section: Introductionmentioning

confidence: 96%

Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas—Same Entity or First Cousins?

et al. 2015

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Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved.

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“…Likewise, the incidence of BRAF V600E is approximately 50% in epithelioid GBM (eGBM), a rare variant of IDH wild-type GBM recognized in the revised 2016 WHO classification. 16 Of note, similar frequencies of BRAF V600E mutations are seen in anaplastic pleomorphic xanthoastrocytoma (aPXA), an entity with overlapping histologic and molecular features to eGBM. DNA methylation profiling of 64 histologically diagnosed eGBMs revealed a subset with a similar expression pattern to PXA that was enriched for BRAF V600E (positive in 80%).…”

Section: Incidencementioning

confidence: 96%

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

Johanns¹,

Ansstas²,

Dahiya³

2018

J Natl Compr Canc Netw

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Use of small molecule inhibitors specific to activating BRAF V600 mutations first demonstrated efficacy in metastatic melanoma.1 Recently, similar results were observed in patients with BRAF-mutated non-small cell lung cancer, leading to FDA approval in June 2017. 2,3 Furthermore, the observation that combining BRAF inhibition (BRAFi) with MEK inhibition (MEKi) leads to improved efficacy and reduced resistance without increased toxicity has set the bar for any future multidrug combination. 4,5 These observations, along with encouraging early-phase data in other histologies, such as papillary thyroid cancer 6 and hairy cell leukemia, 7 which both have high frequencies of BRAF V600E mutations, have led to increasing interest in exploring the role of BRAFi and MEKi in all BRAF-mutated cancers, regardless of histology.8 However, the lack of efficacy in BRAF-mutated colorectal cancer cautions against the agnostic generalization of results with these agents.For primary central nervous system (CNS) tumors, increasing evidence has suggested that BRAFi therapy may be effective. Preliminary results from a phase I/II study of dabrafenib in relapsed or progressive pediatric BRAF V600E-mutated low-grade gliomas reported an 82% clinical benefit rate (stable disease or better at 6 months) among 32 evaluable subjects.9 A subsequent phase II study is underway evaluating the efficacy of combined BRAFi/MEKi in a similar patient population (ClinicalTrials.gov identifier: NCT02684058). Conversely, the efficacy of these agents in adult patients, particularly those with high-grade gliomas (HGGs; WHO grade III) or glioblastoma (GBM; WHO grade IV), which are more common in adults, remains undefined. Two recent publications in JNCCN-an earlier work by Johanns et al 10 and an article by Schreck et al found elsewhere in this issue describing the successful use of combined BRAFi/MEKi therapy in adults with HGG or GBM-contribute to this growing body of literature, suggesting a therapeutic role for these agents in primary CNS disease, and raise several important clinical considerations. IncidenceSeveral large retrospective studies have attempted to estimate the frequency of BRAF mutations in pediatric and adult primary CNS tumors [11][12][13][14][15] ; for adult GBM, the frequency of these mutations is approximately 1% to 3%. Interestingly, the only missense mutation found to date in adult or pediatric primary CNS tumors is the V600E variant. Despite the relatively low frequency of BRAF mutations, it is increased among several subsets of adult patients with GBM: approximately 15% of GBM cases in patients aged 17 to 35 years will harbor a BRAF V600E mutation. 15 Remarkably, BRAF mutations in this cohort were found in similar frequency and were mutually exclusive to other common mutations in IDH1 (17%) and H3F3A (19%), suggesting that BRAF-mutated GBM represents a distinct subgroup. Likewise, the incidence of BRAF V600E is approximately 50% in epithelioid GBM (eGBM), a rare variant of IDH wild-type GBM recognized in the revised 2016 WHO classif...

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Epithelioid GBMs Show a High Percentage of BRAF V600E Mutation

Cited by 237 publications

References 39 publications

BRAF‐V600E immunohistochemistry in a large series of glial and glial–neuronal tumors

BRAF‐V600E immunohistochemistry in a large series of glial and glial–neuronal tumors

Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas—Same Entity or First Cousins?

BRAF-Targeted Therapy in the Treatment of BRAF -Mutant High-Grade Gliomas in Adults

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