Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review

Andrews, Lily; Thornton, Zak; Saincher, Saanwalshah Samir; Yao, Ian Y; Dawson, Sarah; McGuinness, Luke A; Jones, Hayley E; Jefferies, Sarah; Short, Susan C; Cheng, Hung-Yuan; McAleenan, Alexandra; Higgins, Julian P T; Kurian, Kathreena M.

doi:10.1093/neuonc/noab247

Cited by 33 publications

(36 citation statements)

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“…The mutated protein boosts about 500× the MAPK/ERK activation, resulting in uncontrolled cell proliferation and survival (42). BRAFV600E was reported in 69% of epithelioid GBM in a recent systematic review performed on more than 13,000 patients (43).…”

Section: The Turn: Ras-raf Signalingmentioning

confidence: 99%

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

et al. 2022

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Glioblastomas are the most frequent and malignant brain tumor hallmarked by an invariably poor prognosis. They have been classically differentiated into primary isocitrate dehydrogenase 1 or 2 (IDH1 -2) wild-type (wt) glioblastoma (GBM) and secondary IDH mutant GBM, with IDH wt GBMs being commonly associated with older age and poor prognosis. Recently, genetic analyses have been integrated with epigenetic investigations, strongly implementing typing and subtyping of brain tumors, including GBMs, and leading to the new WHO 2021 classification. GBM genomic and epigenomic profile influences evolution, resistance, and therapeutic responses. However, differently from other tumors, there is a wide gap between the refined GBM profiling and the limited therapeutic opportunities. In addition, the different oncogenes and tumor suppressor genes involved in glial cell transformation, the heterogeneous nature of cancer, and the restricted access of drugs due to the blood–brain barrier have limited clinical advancements. This review will summarize the more relevant genetic alterations found in GBMs and highlight their potential role as potential therapeutic targets.

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Section: The Turn: Ras-raf Signalingmentioning

confidence: 99%

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

et al. 2022

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“…4 Standard treatment uses surgery and chemotherapy (typically temozolomide), adjuvant radiotherapy and pharmaceutical intervention such as BRAF inhibitors. 4-5 There is an urgent need for better understanding of gliomagenesis to inform novel therapeutic and preventative strategies because the response and subsequent progression free survival and overall survival of patients is limited.…”

Section: Introductionmentioning

confidence: 99%

Multi-omics Mendelian randomisation using expression, splicing and protein quantitative trait loci: identification of novel drug targets for gliomagenesis

Thornton

Andrews

Zhao

et al. 2022

Preprint

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Genetically predicted changes in molecular traits are associated with genetic liability to glioma risk. We sought to identify and provide evidence for the prioritisation of these traits using a combined two-sample Mendelian randomisation and colocalisation pipeline.We used genetic variants from genome-wide association studies (GWAS) to compare the effects of gene expression, protein abundance and splicing variation on genetic liability to glioma risk.We performed analysis of quantitative trait loci (QTL) (expression QTL [MetaBrain, n=4,119,012]; protein QTL [BrainQTL, n=786,632] and splicing QTL [GTEx, n=166,721]) derived from 15 different brain tissues and summary-level data from eight glioma GWAS (12,496 cases and 18,190 controls).We found robust evidence linking QTL for 25 genes in 15 loci with risk of glioma following relevant sensitivity analysis. We identified four novel genes putatively implicated in glioma risk: BTN3A2 (6p22.2), FAIM (3q22.3), GALNT6 (12q13.13) and GMPPB (3p21.31). Identification of these novel genes may improve understanding in pathogenic mechanisms underlying gliomagenesis and should be followed up in further studies, which may inform novel prevention studies following future clinical trials.

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“…The BRAF gene, located at chromosome 7 (7q34), is a main mediator in the mitogen-activated protein kinase (MAPK) cell signalling pathway and encodes the B-Raf protein, a serine/threonine protein kinase working downstream of the Ras-Raf-MEK-ERK signalling pathway; it is an intracellular signal transducer between extracellular growth stimuli and cellular response [3]. p.V600E is a highly reported oncogenic mutation driver in BRAF (~90%) and occurs through a point mutation (p.T1799A) in exon 15 of BRAF, ending up in the substitution of valine with glutamic acid at codon 600 in most cases [4]. V600E, encountered inside the activation region of BRAF, leads to constitutive activation of the MAPK signalling pathway, leading to hyperactivation (~500x) of the signalling cascade and the uncontrolled division of cells, from insensitivity to negative feedback mechanisms and consequent tumorigenesis [4].…”

Section: Introductionmentioning

confidence: 99%

“…p.V600E is a highly reported oncogenic mutation driver in BRAF (~90%) and occurs through a point mutation (p.T1799A) in exon 15 of BRAF, ending up in the substitution of valine with glutamic acid at codon 600 in most cases [4]. V600E, encountered inside the activation region of BRAF, leads to constitutive activation of the MAPK signalling pathway, leading to hyperactivation (~500x) of the signalling cascade and the uncontrolled division of cells, from insensitivity to negative feedback mechanisms and consequent tumorigenesis [4].…”

Section: Introductionmentioning

confidence: 99%

“…It is commonly held in the category of pleomorphic xanthoastrocytoma and ganglioglioma and can also be found in a subset of pilocytic astrocytomas (PA) and glioblastomas (namely with epithelioid morphology) [3]. Adult patients have shown been to have a lower prevalence of the BRAF p.V600E mutation when compared to paediatric patients (4 vs 7%) [4].…”

Section: Introductionmentioning

confidence: 99%

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Dabrafenib Plus Trametinib: An Impressive Response in an Adult Patient With BRAF V600E-Mutated and Isocitrate Dehydrogenase (IDH) Wild-Type Glioma

Costa¹,

Reis²,

Pinheiro³

et al. 2022

Cureus

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Key molecular alterations found in the diagnosis and prognosis of brain tumours have been revealed by the latest advances in transcriptomic and genome-wide analysis. In-depth studies revealed that alterations of the V-Raf murine sarcoma viral oncogene homolog B (BRAF) could be shared by different brain tumour types. The identification of BRAF p.V600E mutations in gliomas is nowadays of more importance regarding the development of BRAF-targeted inhibitors.This report presents the case of a 37-year-old female with a voluminous expansive neoplastic lesion, extending from the lenticulocapsular region to the medial aspect of the temporal lobe on the left. Pathological examination revealed an astrocytic neoplasm without high-grade histological features in small biopsy fragments. The molecular study revealed the presence of a mutation in the BRAF V600E gene and CDKN2A/2B homozygous deletion. The lesion was partially removed and irradiated. The patient has been on treatment with dabrafenib plus trametinib for 10 months. In addition to reasonable tolerance, she obtained an impressive tumour reduction, which was manifested in the complete resolution of neurological deficits and in the full acquisition of autonomy.The remarkable results reported in this clinical case justify the pressing need to identify new therapeutic targets in gliomas in the current era of precision medicine.

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Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review

Abstract: Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review. Neuro-oncology, [noab247].

Cited by 33 publications

References 46 publications

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

Looking Beyond the Glioblastoma Mask: Is Genomics the Right Path?

Multi-omics Mendelian randomisation using expression, splicing and protein quantitative trait loci: identification of novel drug targets for gliomagenesis

Dabrafenib Plus Trametinib: An Impressive Response in an Adult Patient With BRAF V600E-Mutated and Isocitrate Dehydrogenase (IDH) Wild-Type Glioma

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