BRAF Landscape and Its Implications among Patients with Pediatric Low-Grade Gliomas: A Comprehensive Review of the Literature

Abstract

Low-grade gliomas are the most common intracranial tumor in the pediatric population. Pediatric low-grade gliomas represent a heterogeneous group of tumors. Genetic alterations that result in upregulation of the MAPK/ERK pathway represent most of the genetic landscape of pediatric low-grade gliomas. BRAF-V600E mutant pediatric low-grade gliomas may represent a unique and aggressive subset of tumors that require targeted therapy especially if gross total resection is not feasible. Many patients with pediatric low-grade gliomas have demonstrated successful clinical and radiological responses to BRAF and/or MEK inhibitors. Given the high proportion of patients who fail to respond to the current standard chemotherapy and radiotherapy, these targeted therapies should be considered in future trials and further investigations. In this review of the literature, we summarize the molecular status of BRAF alterations among patients with pediatric low-grade gliomas and provide an update on previous and current BRAF and MEK inhibitors clinical trials.

Keywords

pediatric - low-grade glioma - BRAF - BRAF inhibitors - MEK inhibitors

Publication History

Received: 07 February 2023

Accepted: 02 March 2023

Article published online:
12 April 2023

• References

• 1 Hemmati HD, Nakano I, Lazareff JA. et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 2003; 100 (25) 15178-15183
• 2 Ostrom QT, Cioffi G, Gittleman H. et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2012-2016. Neuro-oncol 2019; 21 (Suppl. 05) v1-v100
• 3 Chalil A, Ramaswamy V. Low grade gliomas in children. J Child Neurol 2016; 31 (04) 517-522
• 4 Louis DN, Perry A, Wesseling P. et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncol 2021; 23 (08) 1231-1251
• 5 Bergthold G, Bandopadhayay P, Bi WL. et al. Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta 2014; 1845 (02) 294-307
• 6 Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro-oncol 2012; 14 (suppl 5, suppl 5): v1-v49
• 7 Bauchet L, Rigau V, Mathieu-Daudé H. et al; Société Française de Neurochirurgie Pédiatrique, Société Française de Neurochirurgie, Société Française de Neuropathologie, Association des Neuro-Oncologues d'Expression Française. Clinical epidemiology for childhood primary central nervous system tumors. J Neurooncol 2009; 92 (01) 87-98
• 8 Kaatsch P, Rickert CH, Kühl J, Schüz J, Michaelis J. Population-based epidemiologic data on brain tumors in German children. Cancer 2001; 92 (12) 3155-3164
• 9 Radner H, Blümcke I, Reifenberger G, Wiestler OD. [The new WHO classification of tumors of the nervous system 2000. Pathology and genetics]. Pathologe 2002; 23 (04) 260-283
• 10 Amatya VJ, Akazawa R, Sumimoto Y, Takeshima Y, Inai K. Clinicopathological and immunohistochemical features of three pilomyxoid astrocytomas: comparative study with 11 pilocytic astrocytomas. Pathol Int 2009; 59 (02) 80-85
• 11 Forbes JA, Mobley BC, O'Lynnger TM. et al. Pediatric cerebellar pilomyxoid-spectrum astrocytomas. J Neurosurg Pediatr 2011; 8 (01) 90-96
• 12 Rees J, Watt H, Jäger HR. et al. Volumes and growth rates of untreated adult low-grade gliomas indicate risk of early malignant transformation. Eur J Radiol 2009; 72 (01) 54-64
• 13 Youland RS, Brown PD, Giannini C, Parney IF, Uhm JH, Laack NN. Adult low-grade glioma: 19-year experience at a single institution. Am J Clin Oncol 2013; 36 (06) 612-619
• 14 Johnson DR, Brown PD, Galanis E, Hammack JE. Pilocytic astrocytoma survival in adults: analysis of the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. J Neurooncol 2012; 108 (01) 187-193
• 15 Gunny RS, Hayward RD, Phipps KP, Harding BN, Saunders DE. Spontaneous regression of residual low-grade cerebellar pilocytic astrocytomas in children. Pediatr Radiol 2005; 35 (11) 1086-1091
• 16 Rozen WM, Joseph S, Lo PA. Spontaneous regression of low-grade gliomas in pediatric patients without neurofibromatosis. Pediatr Neurosurg 2008; 44 (04) 324-328
• 17 Schmandt SM, Packer RJ, Vezina LG, Jane J. Spontaneous regression of low-grade astrocytomas in childhood. Pediatr Neurosurg 2000; 32 (03) 132-136
• 18 Bandopadhayay P, Bergthold G, London WB. et al. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer 2014; 61 (07) 1173-1179
• 19 Juratli TA, Kirsch M, Robel K. et al. IDH mutations as an early and consistent marker in low-grade astrocytomas WHO grade II and their consecutive secondary high-grade gliomas. J Neurooncol 2012; 108 (03) 403-410
• 20 Kim YH, Nobusawa S, Mittelbronn M. et al. Molecular classification of low-grade diffuse gliomas. Am J Pathol 2010; 177 (06) 2708-2714
• 21 Lin A, Rodriguez FJ, Karajannis MA. et al. BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants. J Neuropathol Exp Neurol 2012; 71 (01) 66-72
• 22 MacConaill LE, Campbell CD, Kehoe SM. et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One 2009; 4 (11) e7887
• 23 Tian Y, Rich BE, Vena N. et al. Detection of KIAA1549-BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas. J Mol Diagn 2011; 13 (06) 669-677
• 24 Zhang J, Wu G, Miller CP. et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013; 45 (06) 602-612
• 25 Dodgshun AJ, SantaCruz N, Hwang J. et al. Disseminated glioneuronal tumors occurring in childhood: treatment outcomes and BRAF alterations including V600E mutation. J Neurooncol 2016; 128 (02) 293-302
• 26 Davies H, Bignell GR, Cox C. et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417 (6892): 949-954
• 27 Schreck KC, Grossman SA, Pratilas CA. BRAF mutations and the utility of RAF and MEK inhibitors in primary brain tumors. Cancers (Basel) 2019; 11 (09) 1262
• 28 Cerami E, Gao J, Dogrusoz U. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2 (05) 401-404
• 29 Lito P, Pratilas CA, Joseph EW. et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 2012; 22 (05) 668-682
• 30 Pratilas CA, Taylor BS, Ye Q. et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A 2009; 106 (11) 4519-4524
• 31 Yao Z, Yaeger R, Rodrik-Outmezguine VS. et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 2017; 548 (7666): 234-238
• 32 Yao Z, Torres NM, Tao A. et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell 2015; 28 (03) 370-383
• 33 Pratt D, Camelo-Piragua S, McFadden K. et al. BRAF activating mutations involving the β3-αC loop in V600E-negative anaplastic pleomorphic xanthoastrocytoma. Acta Neuropathol Commun 2018; 6 (01) 24
• 34 Foster SA, Whalen DM, Özen A. et al. Activation mechanism of oncogenic deletion mutations in BRAF, EGFR, and HER2. Cancer Cell 2016; 29 (04) 477-493
• 35 Chen SH, Zhang Y, Van Horn RD. et al. Oncogenic BRAF deletions that function as homodimers and are sensitive to inhibition by RAF dimer inhibitor LY3009120. Cancer Discov 2016; 6 (03) 300-315
• 36 Jones DT, Kocialkowski S, Liu L. et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008; 68 (21) 8673-8677
• 37 Cin H, Meyer C, Herr R. et al. Oncogenic FAM131B-BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma. Acta Neuropathol 2011; 121 (06) 763-774
• 38 Forshew T, Tatevossian RG, Lawson AR. et al. Activation of the ERK/MAPK pathway: a signature genetic defect in posterior fossa pilocytic astrocytomas. J Pathol 2009; 218 (02) 172-181
• 39 Jones DT, Hutter B, Jäger N. et al; International Cancer Genome Consortium PedBrain Tumor Project. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 2013; 45 (08) 927-932
• 40 Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 2009; 28 (20) 2119-2123
• 41 Bar EE, Lin A, Tihan T, Burger PC, Eberhart CG. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. J Neuropathol Exp Neurol 2008; 67 (09) 878-887
• 42 Pfister S, Janzarik WG, Remke M. et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 2008; 118 (05) 1739-1749
• 43 Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro-oncol 2012; 14 (06) 777-789
• 44 de Blank P, Bandopadhayay P, Haas-Kogan D, Fouladi M, Fangusaro J. Management of pediatric low-grade glioma. Curr Opin Pediatr 2019; 31 (01) 21-27
• 45 Sievert AJ, Jackson EM, Gai X. et al. Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene. Brain Pathol 2009; 19 (03) 449-458
• 46 Kaul A, Chen YH, Emnett RJ, Dahiya S, Gutmann DH. Pediatric glioma-associated KIAA1549:BRAF expression regulates neuroglial cell growth in a cell type-specific and mTOR-dependent manner. Genes Dev 2012; 26 (23) 2561-2566
• 47 Tran NH, Wu X, Frost JA. B-Raf and Raf-1 are regulated by distinct autoregulatory mechanisms. J Biol Chem 2005; 280 (16) 16244-16253
• 48 Wan PT, Garnett MJ, Roe SM. et al; Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004; 116 (06) 855-867
• 49 Dougherty MJ, Santi M, Brose MS. et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro-oncol 2010; 12 (07) 621-630
• 50 Schindler G, Capper D, Meyer J. et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 2011; 121 (03) 397-405
• 51 Horbinski C. To BRAF or not to BRAF: is that even a question anymore?. J Neuropathol Exp Neurol 2013; 72 (01) 2-7
• 52 Gronych J, Korshunov A, Bageritz J. et al. An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice. J Clin Invest 2011; 121 (04) 1344-1348
• 53 Xu J, Lai M, Li S. et al. Radiomics features based on MRI predict BRAF V600E mutation in pediatric low-grade gliomas: a non-invasive method for molecular diagnosis. Clin Neurol Neurosurg 2022; 222: 107478
• 54 Brastianos PK, Shankar GM, Gill CM. et al. Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy. J Natl Cancer Inst 2015; 108 (02) djv310
• 55 García-Romero N, Carrión-Navarro J, Areal-Hidalgo P. et al. BRAF V600E detection in liquid biopsies from pediatric central nervous system tumors. Cancers (Basel) 2019; 12 (01) 66
• 56 Tan JY, Wijesinghe IVS, Alfarizal Kamarudin MN, Parhar I. Paediatric gliomas: BRAF and Histone H3 as biomarkers, therapy and perspective of liquid biopsies. Cancers (Basel) 2021; 13 (04) 607
• 57 Ramaglia A, Tortora D, Mankad K. et al. Role of diffusion weighted imaging for differentiating cerebral pilocytic astrocytoma and ganglioglioma BRAF V600E-mutant from wild type. Neuroradiology 2020; 62 (01) 71-80
• 58 Lambin P, Rios-Velazquez E, Leijenaar R. et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur J Cancer 2012; 48 (04) 441-446
• 59 Kumar V, Gu Y, Basu S. et al. Radiomics: the process and the challenges. Magn Reson Imaging 2012; 30 (09) 1234-1248
• 60 Lao J, Chen Y, Li ZC. et al. A deep learning-based radiomics model for prediction of survival in glioblastoma multiforme. Sci Rep 2017; 7 (01) 10353
• 61 Akbari H, Bakas S, Pisapia JM. et al. In vivo evaluation of EGFRvIII mutation in primary glioblastoma patients via complex multiparametric MRI signature. Neuro-oncol 2018; 20 (08) 1068-1079
• 62 Raabe EH, Lim KS, Kim JM. et al. BRAF activation induces transformation and then senescence in human neural stem cells: a pilocytic astrocytoma model. Clin Cancer Res 2011; 17 (11) 3590-3599
• 63 Rodriguez EF, Scheithauer BW, Giannini C. et al. PI3K/AKT pathway alterations are associated with clinically aggressive and histologically anaplastic subsets of pilocytic astrocytoma. Acta Neuropathol 2011; 121 (03) 407-420
• 64 Schiffman JD, Hodgson JG, VandenBerg SR. et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res 2010; 70 (02) 512-519
• 65 Margraf LR, Gargan L, Butt Y, Raghunathan N, Bowers DC. Proliferative and metabolic markers in incompletely excised pediatric pilocytic astrocytomas—an assessment of 3 new variables in predicting clinical outcome. Neuro-oncol 2011; 13 (07) 767-774
• 66 Huillard E, Hashizume R, Phillips JJ. et al. Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A 2012; 109 (22) 8710-8715
• 67 Lassaletta A, Zapotocky M, Mistry M. et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol 2017; 35 (25) 2934-2941
• 68 Berg M, Nordgaard O, Kørner H. et al. Molecular subtypes in stage II-III colon cancer defined by genomic instability: early recurrence-risk associated with a high copy-number variation and loss of RUNX3 and CDKN2A. PLoS One 2015; 10 (04) e0122391
• 69 Alhejaily A, Day AG, Feilotter HE, Baetz T, Lebrun DP. Inactivation of the CDKN2A tumor-suppressor gene by deletion or methylation is common at diagnosis in follicular lymphoma and associated with poor clinical outcome. Clin Cancer Res 2014; 20 (06) 1676-1686
• 70 Mistry M, Zhukova N, Merico D. et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol 2015; 33 (09) 1015-1022
• 71 Jacob K, Quang-Khuong DA, Jones DT. et al. Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 2011; 17 (14) 4650-4660
• 72 Penman CL, Faulkner C, Lowis SP, Kurian KM. Current understanding of BRAF alterations in diagnosis, prognosis, and therapeutic targeting in pediatric low-grade gliomas. Front Oncol 2015; 5: 54
• 73 Hawkins C, Walker E, Mohamed N. et al. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 2011; 17 (14) 4790-4798
• 74 Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF. Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 2010; 119 (05) 641-649
• 75 Laviv Y, Toledano H, Michowiz S. et al. BRAF, GNAQ, and GNA11 mutations and copy number in pediatric low-grade glioma. FEBS Open Bio 2012; 2: 129-134
• 76 Lin F, Cordes K, Li L. et al. Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia-reperfusion injury in mice. J Am Soc Nephrol 2003; 14 (05) 1188-1199
• 77 Ho CY, Mobley BC, Gordish-Dressman H. et al. A clinicopathologic study of diencephalic pediatric low-grade gliomas with BRAF V600 mutation. Acta Neuropathol 2015; 130 (04) 575-585
• 78 Ater JL, Zhou T, Holmes E. et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol 2012; 30 (21) 2641-2647
• 79 Merchant TE, Kun LE, Wu S, Xiong X, Sanford RA, Boop FA. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol 2009; 27 (22) 3598-3604
• 80 Gorodezki D, Zipfel J, Queudeville M. et al. Resection extent and BRAF V600E mutation status determine postoperative tumor growth velocity in pediatric low-grade glioma: results from a single-center cohort analysis. J Neurooncol 2022; 160 (03) 567-576
• 81 Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. Acta Neuropathol 2005; 109 (01) 93-108
• 82 Colin C, Padovani L, Chappé C. et al. Outcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution. Neuropathol Appl Neurobiol 2013; 39 (06) 693-705
• 83 Stokland T, Liu JF, Ironside JW. et al. A multivariate analysis of factors determining tumor progression in childhood low-grade glioma: a population-based cohort study (CCLG CNS9702). Neuro-oncol 2010; 12 (12) 1257-1268
• 84 Fernandez C, Figarella-Branger D, Girard N. et al. Pilocytic astrocytomas in children: prognostic factors—a retrospective study of 80 cases. Neurosurgery 2003; 53 (03) 544-553 , discussion 554–555
• 85 Tchoghandjian A, Fernandez C, Colin C. et al. Pilocytic astrocytoma of the optic pathway: a tumour deriving from radial glia cells with a specific gene signature. Brain 2009; 132 (Pt 6): 1523-1535
• 86 Tibbetts KM, Emnett RJ, Gao F, Perry A, Gutmann DH, Leonard JR. Histopathologic predictors of pilocytic astrocytoma event-free survival. Acta Neuropathol 2009; 117 (06) 657-665
• 87 Rodriguez FJ, Perry A, Rosenblum MK. et al. Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. Acta Neuropathol 2012; 124 (05) 627-641
• 88 Preuss M, Christiansen H, Merkenschlager A. et al. Disseminated oligodendroglial-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity [corrected]. [corrected] J Neurooncol 2015; 124 (01) 65-74
• 89 Johanns TM, Ansstas G, Dahiya S. BRAF-targeted therapy in the treatment of BRAF-mutant high-grade gliomas in adults. J Natl Compr Canc Netw 2018; 16 (04) 451-454
• 90 Leonetti A, Facchinetti F, Rossi G. et al. BRAF in non-small cell lung cancer (NSCLC): pickaxing another brick in the wall. Cancer Treat Rev 2018; 66: 82-94
• 91 Subbiah V, Baik C, Kirkwood JM. Clinical development of BRAF plus MEK inhibitor combinations. Trends Cancer 2020; 6 (09) 797-810
• 92 Tiacci E, De Carolis L, Simonetti E. et al. Vemurafenib plus rituximab in refractory or relapsed hairy-cell leukemia. N Engl J Med 2021; 384 (19) 1810-1823
• 93 Kolb EA, Gorlick R, Houghton PJ. et al. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the pediatric preclinical testing program. Pediatr Blood Cancer 2010; 55 (04) 668-677
• 94 Nicolaides TP, Li H, Solomon DA. et al. Targeted therapy for BRAFV600E malignant astrocytoma. Clin Cancer Res 2011; 17 (24) 7595-7604
• 95 Hargrave DR, Bouffet E, Tabori U. et al. Efficacy and safety of Dabrafenib in pediatric patients with BRAF V600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa Study. Clin Cancer Res 2019; 25 (24) 7303-7311
• 96 Long GV, Trefzer U, Davies MA. et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13 (11) 1087-1095
• 97 Landi DB, Ziegler DS, Franson AF. et al. FIREFLY-1 (PNOC 026): a phase 2 study to evaluate the safety and efficacy of tovorafenib (DAY101) in pediatric patients with RAF-altered recurrent or progressive low-grade glioma or advanced solid tumors. American Society of Clinical Oncology; 2022
• 98 Di Nunno V, Gatto L, Tosoni A, Bartolini S, Franceschi E. Implications of BRAF V600E mutation in gliomas: Molecular considerations, prognostic value and treatment evolution. Front Oncol 2023; 12: 1067252
• 99 Wen PY, Weller M, Lee EQ. et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro-oncol 2020; 22 (08) 1073-1113
• 100 Davies MA, Saiag P, Robert C. et al. Dabrafenib plus trametinib in patients with BRAF^V600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol 2017; 18 (07) 863-873
• 101 Wen PY, Stein A, van den Bent M. et al. Dabrafenib plus trametinib in patients with BRAF^V600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol 2022; 23 (01) 53-64
• 102 Bouffet E, Hansford J, Garré ML. et al. Primary analysis of a phase II trial of dabrafenib plus trametinib (dab+ tram) in BRAF V600–mutant pediatric low-grade glioma (pLGG). American Society of Clinical Oncology; 2022
• 103 Karajannis MA, Legault G, Fisher MJ. et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro-oncol 2014; 16 (10) 1408-1416
• 104 Sievert AJ, Lang SS, Boucher KL. et al. Paradoxical activation and RAF inhibitor resistance of BRAF protein kinase fusions characterizing pediatric astrocytomas. Proc Natl Acad Sci U S A 2013; 110 (15) 5957-5962
• 105 Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010; 464 (7287): 427-430
• 106 Hatzivassiliou G, Song K, Yen I. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464 (7287): 431-435
• 107 Pekmezci M, Villanueva-Meyer JE, Goode B. et al. The genetic landscape of ganglioglioma. Acta Neuropathol Commun 2018; 6 (01) 47
• 108 Koelsche C, Wöhrer A, Jeibmann A. et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol 2013; 125 (06) 891-900
• 109 Brandner S, von Deimling A. Diagnostic, prognostic and predictive relevance of molecular markers in gliomas. Neuropathol Appl Neurobiol 2015; 41 (06) 694-720
• 110 Blessing MM, Blackburn PR, Balcom JR. et al. Novel BRAF alteration in desmoplastic infantile ganglioglioma with response to targeted therapy. Acta Neuropathol Commun 2018; 6 (01) 118
• 111 Chappé C, Padovani L, Scavarda D. et al. Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression. Brain Pathol 2013; 23 (05) 574-583
• 112 Matsumura N, Nobusawa S, Ito J. et al. Multiplex ligation-dependent probe amplification analysis is useful for detecting a copy number gain of the FGFR1 tyrosine kinase domain in dysembryoplastic neuroepithelial tumors. J Neurooncol 2019; 143 (01) 27-33
• 113 Deng MY, Sill M, Chiang J. et al. Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. Acta Neuropathol 2018; 136 (02) 239-253
• 114 Terashima K, Chow K, Jones J. et al. Long-term outcome of centrally located low-grade glioma in children. Cancer 2013; 119 (14) 2630-2638
• 115 Cruz GR, Dias Oliveira I, Moraes L. et al. Analysis of KIAA1549-BRAF fusion gene expression and IDH1/IDH2 mutations in low grade pediatric astrocytomas. J Neurooncol 2014; 117 (02) 235-242
• 116 Yang RR, Aibaidula A, Wang WW. et al. Pediatric low-grade gliomas can be molecularly stratified for risk. Acta Neuropathol 2018; 136 (04) 641-655
• 117 Carey SS, Sadighi Z, Wu S. et al. Evaluating pediatric spinal low-grade gliomas: a 30-year retrospective analysis. J Neurooncol 2019; 145 (03) 519-529
• 118 Nellan A, Wright E, Campbell K. et al. Retrospective analysis of combination carboplatin and vinblastine for pediatric low-grade glioma. J Neurooncol 2020; 148 (03) 569-575
• 119 Falkenstein F, Gessi M, Kandels D. et al. Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II-Report from the German/Swiss SIOP-LGG 2004 cohort. Int J Cancer 2020; 147 (08) 2159-2175