Epithelioid glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis

Korshunov, Andrey; Chávez, Lukas; Sharma, Tanvi; Ryzhova, Marina; Schrimpf, Daniel; Stichel, Damian; Capper, David; Sturm, Dominik; Kool, Marcel; Habel, Antje; Kleinschmidt‐DeMasters, Bette K.; Rosenblum, Marc K.; Absalyamova, O V; Golanov, Andrey; Lichter, Peter; Pfister, Stefan M.; Jones, David; Perry, Arie; Deimling, Andreas von

doi:10.1111/bpa.12566

Cited by 104 publications

(102 citation statements)

References 28 publications

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“…It has been suggested that a subset of anaplastic PXA and epithelioid GBM share several genetic features including BRAF V600E mutations and may be closely related to each other, if not classified in the same entity . In contrast, methylation profiling showed that epithelioid GBM may be divided into PXA and GBM, suggesting that there may be distinct subgroups . Our case strongly suggests that DNA methylation‐based diagnosis can more precisely classify anaplastic PXA, as has recently been proposed .…”

Section: Discussionsupporting

confidence: 70%

“…profiling showed that epithelioid GBM may be divided into PXA and GBM, suggesting that there may be distinct subgroups. 9 Our case strongly suggests that DNA methylation-based diagnosis can more precisely classify anaplastic PXA, as has recently been proposed. 5 It is unlikely that histology alone is sufficient to diagnose anaplastic PXA, as pleomorphic gliomas with anaplastic features include both anaplastic PXA and epithelioid GBM.…”

Section: A S E Rep Ortsupporting

confidence: 72%

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Genome‐wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma

et al. 2019

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In the revised World Health Organization classification 2016, anaplastic pleomorphic xanthoastrocytoma (PXA) has been newly defined as a variant of the PXA entity. Furthermore, some anaplastic PXA were reported to have extremely poor prognosis which showed a type of pediatric glioblastoma (GBM) molecular profile. Recent integrated molecular classification for primary central nervous system tumors proposed some differences between histological and molecular features. Herein, in a genome‐wide molecular analysis, we show an extreme aggressive anaplastic PXA that resulted in a pediatric GBM molecular profile. A full implementation of the molecular approach is the key to predict prognosis and decide the treatment strategy for anaplastic PXA.

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Section: Discussionsupporting

confidence: 70%

Section: A S E Rep Ortsupporting

confidence: 72%

Genome‐wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma

et al. 2019

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“…To date, a single DNA methylation pattern sufficiently distinct for robust tumour classification has been identified for pleomorphic xanthoastrocytoma (PXA) . Currently, WHO grade II and III PXA share this DNA methylation class that was therefore named (anaplastic) pleomorphic xanthoastrocytoma .…”

Section: Methylation Profiling Of Established Paediatric Brain Tumourmentioning

confidence: 99%

“…Currently, WHO grade II and III PXA share this DNA methylation class that was therefore named (anaplastic) pleomorphic xanthoastrocytoma . DNA methylation indicates that PXA may be considered as something like the chameleon of brain tumours, as tumours with this distinct molecular profile have been identified in substantial numbers among histological series of paediatric glioblastomas epithelioid glioblastomas and astroblastomas , and at lower frequency among embryonal tumours , gangliogliomas and AT/RTs . Thus, in contrast to several other discussed tumours (e.g.…”

Section: Methylation Profiling Of Established Paediatric Brain Tumourmentioning

confidence: 99%

Invited Review: DNA methylation‐based classification of paediatric brain tumours

Perez

Capper

2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 28-47 DNA methylation-based classification of paediatric brain tumours DNA methylation-based machine learning algorithms represent powerful diagnostic tools that are currently emerging for several fields of tumour classification. For various reasons, paediatric brain tumours have been the main driving forces behind this rapid development and brain tumour classification tools are likely further advanced than in any other field of cancer diagnostics. In this review, we will discuss the main characteristics that were important for this rapid advance, namely the high clinical need for improvement of paediatric brain tumour diagnostics, the robustness of methylated DNA and the consequential possibility to generate high-quality molecular data from archival formalin-fixed paraffin-embedded pathology specimens, the implementation of a single array platform by most laboratories allowing data exchange and data pooling to an unprecedented extent, as well as the high suitability of the data format for machine learning. We will further discuss the four most central output qualities of DNA methylation profiling in a diagnostic setting (tumour classification, tumour sub-classification, copy number analysis and guidance for additional molecular testing) individually for the most frequent types of paediatric brain tumours. Lastly, we will discuss DNA methylation profiling as a tool for the detection of new paediatric brain tumour classes and will give an overview of the rapidly growing family of new tumours identified with the aid of this technique.

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“…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%). 17 Therefore, although the histologic distinction between eGBM and aPXA remains debatable based on morphology alone, the presence of either of these features in HGG (ie, epithelioid or PXA-like characteristics), as well as any IDH wild-type GBM, particularly in a patient aged <35 years, should trigger routine screening for the presence of a BRAF V600E mutation. …”

Section: Incidencementioning

confidence: 99%

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 glioblastomas stratify into established diagnostic subsets upon integrated molecular analysis

Cited by 104 publications

References 28 publications

Genome‐wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma

Genome‐wide DNA methylation profiling shows molecular heterogeneity of anaplastic pleomorphic xanthoastrocytoma

Invited Review: DNA methylation‐based classification of paediatric brain tumours

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

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