{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T15:59:22Z","timestamp":1774972762854,"version":"3.50.1"},"reference-count":104,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010699","name":"Monash University Malaysia","doi-asserted-by":"publisher","award":["Not applicable"],"award-info":[{"award-number":["Not applicable"]}],"id":[{"id":"10.13039\/501100010699","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Paediatric gliomas categorised as low- or high-grade vary markedly from their adult counterparts, and denoted as the second most prevalent childhood cancers after leukaemia. As compared to adult gliomas, the studies of diagnostic and prognostic biomarkers, as well as the development of therapy in paediatric gliomas, are still in their infancy. A body of evidence demonstrates that B-Raf Proto-Oncogene or V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and histone H3 mutations are valuable biomarkers for paediatric low-grade gliomas (pLGGs) and high-grade gliomas (pHGGs). Various diagnostic methods involving fluorescence in situ hybridisation, whole-genomic sequencing, PCR, next-generation sequencing and NanoString are currently used for detecting BRAF and histone H3 mutations. Additionally, liquid biopsies are gaining popularity as an alternative to tumour materials in detecting these biomarkers, but still, they cannot fully replace solid biopsies due to several limitations. Although histone H3 mutations are reliable prognosis biomarkers in pHGGs, children with these mutations have a dismal prognosis. Conversely, the role of BRAF alterations as prognostic biomarkers in pLGGs is still in doubt due to contradictory findings. The BRAF V600E mutation is seen in the majority of pLGGs (as seen in pleomorphic xanthoastrocytoma and gangliomas). By contrast, the H3K27M mutation is found in the majority of paediatric diffuse intrinsic pontine glioma and other midline gliomas in pHGGs. pLGG patients with a BRAF V600E mutation often have a lower progression-free survival rate in comparison to wild-type pLGGs when treated with conventional therapies. BRAF inhibitors (Dabrafenib and Vemurafenib), however, show higher overall survival and tumour response in BRAF V600E mutated pLGGs than conventional therapies in some studies. To date, targeted therapy and precision medicine are promising avenues for paediatric gliomas with BRAF V600E and diffuse intrinsic pontine glioma with the H3K27M mutations. Given these shortcomings in the current treatments of paediatric gliomas, there is a dire need for novel therapies that yield a better therapeutic response. The present review discusses the diagnostic tools and the perspective of liquid biopsies in the detection of BRAF V600E and H3K27M mutations. An in-depth understanding of these biomarkers and the therapeutics associated with the respective challenges will bridge the gap between paediatric glioma patients and the development of effective therapies.<\/jats:p>","DOI":"10.3390\/cancers13040607","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T01:15:50Z","timestamp":1612401350000},"page":"607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies"],"prefix":"10.3390","volume":"13","author":[{"given":"Jean Yin","family":"Tan","sequence":"first","affiliation":[{"name":"Brain Research Institute Monash Sunway, Jeffrey Cheah School of Medicine and Health Science, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ipalawattage Vindya Stephnie","family":"Wijesinghe","sequence":"additional","affiliation":[{"name":"Brain Research Institute Monash Sunway, Jeffrey Cheah School of Medicine and Health Science, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2505-1018","authenticated-orcid":false,"given":"Muhamad Noor","family":"Alfarizal Kamarudin","sequence":"additional","affiliation":[{"name":"Brain Research Institute Monash Sunway, Jeffrey Cheah School of Medicine and Health Science, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ishwar","family":"Parhar","sequence":"additional","affiliation":[{"name":"Brain Research Institute Monash Sunway, Jeffrey Cheah School of Medicine and Health Science, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"v1","DOI":"10.1093\/neuonc\/noz150","article-title":"CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012\u20132016","volume":"21","author":"Ostrom","year":"2019","journal-title":"Neuro-Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization classification of tumors of the central nervous system: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.ncl.2018.04.003","article-title":"World Health Organization 2016 classification of central nervous system tumors","volume":"36","author":"Diamandis","year":"2018","journal-title":"Neurol. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ghizoni, E., Naccarato, C.R.M., and Mathias, R.N. (2019). Brain Tumors in Children. Fundamentals of Neurosurgery, Springer.","DOI":"10.1007\/978-3-030-17649-5_18"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gajjar, A., Reaman, G.H., Racadio, J.M., and Smith, F.O. (2018). Brain Tumors in Children, Springer.","DOI":"10.1007\/978-3-319-43205-2"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1093\/neuonc\/noz022","article-title":"Molecular profiling and targeted therapy in pediatric gliomas: Review and consensus recommendations","volume":"21","author":"Miklja","year":"2019","journal-title":"Neuro-Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1007\/s00401-015-1410-7","article-title":"Pilocytic astrocytoma: Pathology, molecular mechanisms and markers","volume":"129","author":"Collins","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1007\/s00018-011-0898-9","article-title":"MAPK pathway activation in pilocytic astrocytoma","volume":"69","author":"Jones","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/ng.2611","article-title":"Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas","volume":"45","author":"Zhang","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1158\/1078-0432.CCR-11-0034","article-title":"BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma","volume":"17","author":"Hawkins","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1007\/s00381-019-04282-1","article-title":"Pilocytic astrocytomas: BRAFV600E and BRAF fusion expression patterns in pediatric and adult age groups","volume":"35","author":"Kurani","year":"2019","journal-title":"Child\u2019s Nerv. Syst."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2934","DOI":"10.1200\/JCO.2016.71.8726","article-title":"Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas","volume":"35","author":"Lassaletta","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s10014-019-00340-3","article-title":"Molecular genetics and therapeutic targets of pediatric low-grade gliomas","volume":"36","author":"Tateishi","year":"2019","journal-title":"Brain Tumor Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1097\/MOP.0000000000000717","article-title":"Management of pediatric low-grade glioma","volume":"31","author":"Bandopadhayay","year":"2019","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s00401-007-0243-4","article-title":"The 2007 WHO classification of tumours of the central nervous system","volume":"114","author":"Louis","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/ng.1102","article-title":"Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas","volume":"44","author":"Wu","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nature10833","article-title":"Driver mutations in histone H3. 3 and chromatin remodelling genes in paediatric glioblastoma","volume":"482","author":"Schwartzentruber","year":"2012","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1101\/gad.309013.117","article-title":"Oncohistones: Drivers of pediatric cancers","volume":"31","author":"Mohammad","year":"2017","journal-title":"Genes Dev."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Hennika, T., Hu, G., Olaciregui, N.G., Barton, K.L., Ehteda, A., Chitranjan, A., Chang, C., Gifford, A.J., Tsoli, M., and Ziegler, D.S. (2017). Pre-clinical study of panobinostat in xenograft and genetically engineered murine diffuse intrinsic pontine glioma models. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169485"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/neuonc\/nox149","article-title":"Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location","volume":"20","author":"Karremann","year":"2018","journal-title":"Neuro-Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/nan.12591","article-title":"Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high-grade gliomas","volume":"46","author":"Kasper","year":"2020","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1111\/bpa.12023","article-title":"Chromatin Remodeling Defects in Pediatric and Young Adult Glioblastoma: A Tale of a Variant H istone 3 Tail","volume":"23","author":"Fontebasso","year":"2013","journal-title":"Brain Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1126\/science.1232245","article-title":"Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma","volume":"340","author":"Lewis","year":"2013","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s11060-017-2393-0","article-title":"Pediatric high-grade glioma: Current molecular landscape and therapeutic approaches","volume":"134","author":"Braunstein","year":"2017","journal-title":"J. Neuro-Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s11060-014-1448-8","article-title":"Diffuse intrinsic pontine glioma: A reassessment","volume":"119","author":"Robison","year":"2014","journal-title":"J. Neuro-Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/neuonc\/noy070","article-title":"Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma","volume":"20","author":"Gupta","year":"2018","journal-title":"Neuro-Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11940-019-0577-y","article-title":"Diffuse intrinsic pontine glioma: From diagnosis to next-generation clinical trials","volume":"21","author":"Vitanza","year":"2019","journal-title":"Curr. Treat. Options Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1007\/s00401-011-0817-z","article-title":"Oncogenic FAM131B\u2013BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma","volume":"121","author":"Cin","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Myall, N.J., and Padda, S.K. (2019). BRAF: Novel Therapies for an Emerging Target. Targeted Therapies for Lung Cancer, Springer.","DOI":"10.1007\/978-3-030-17832-1_4"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Penman, C.L., Faulkner, C., Lowis, S.P., and Kurian, K.M. (2015). Current understanding of BRAF alterations in diagnosis, prognosis, and therapeutic targeting in pediatric low-grade gliomas. Front. Oncol., 5.","DOI":"10.3389\/fonc.2015.00054"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s11060-016-2333-4","article-title":"Combined BRAF V600E and MEK blockade for BRAF V600E-mutant gliomas","volume":"131","author":"Zhang","year":"2017","journal-title":"J. Neuro-Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"a001396","DOI":"10.1101\/mcs.a001396","article-title":"A novel, potentially targetable TMEM106B-BRAF fusion in pleomorphic xanthoastrocytoma","volume":"3","author":"Hsiao","year":"2017","journal-title":"Mol. Case Stud."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tutuka, C.S., Andrews, M.C., Mariadason, J.M., Ioannidis, P., Hudson, C., Cebon, J., and Behren, A. (2017). PLX8394, a new generation BRAF inhibitor, selectively inhibits BRAF in colonic adenocarcinoma cells and prevents paradoxical MAPK pathway activation. Mol. Cancer, 16.","DOI":"10.1186\/s12943-017-0684-x"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"See, W.L., and Mukherjee, J. (2018). Targeting the RAS-RAF-MEK-ERK signaling pathway in gliomas. Handbook of Brain Tumor Chemotherapy, Molecular Therapeutics, and Immunotherapy, Elsevier.","DOI":"10.1016\/B978-0-12-812100-9.00022-X"},{"key":"ref_35","first-page":"51","article-title":"BRAF alterations in primary brain tumors","volume":"26","author":"Maraka","year":"2018","journal-title":"Discov. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1593\/tlo.12328","article-title":"Analysis of the BRAFV600E mutation in central nervous system tumors","volume":"5","author":"Myung","year":"2012","journal-title":"Transl. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s00432-015-2006-2","article-title":"Analysis of IDH1-R132 mutation, BRAF V600 mutation and KIAA1549\u2013BRAF fusion transcript status in central nervous system tumors supports pediatric tumor classification","volume":"142","author":"Gierke","year":"2016","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Behling, F., and Schittenhelm, J. (2019). Oncogenic BRAF alterations and their role in brain tumors. Cancers, 11.","DOI":"10.3390\/cancers11060794"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.jmoldx.2011.07.002","article-title":"Detection of KIAA1549-BRAF fusion transcripts in formalin-fixed paraffin-embedded pediatric low-grade gliomas","volume":"13","author":"Tian","year":"2011","journal-title":"J. Mol. Diagn."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1158\/1535-7163.MCT-10-0799","article-title":"BRAFV600E: Implications for carcinogenesis and molecular therapy","volume":"10","author":"Sheils","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Ryall, S., Tabori, U., and Hawkins, C. (2020). Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol. Commun., 8.","DOI":"10.1186\/s40478-020-00902-z"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.1038\/s41388-018-0171-x","article-title":"Classifying BRAF alterations in cancer: New rational therapeutic strategies for actionable mutations","volume":"37","author":"Dankner","year":"2018","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/nm.4369","article-title":"An approach to suppress the evolution of resistance in BRAF V600E-mutant cancer","volume":"23","author":"Xue","year":"2017","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1093\/jnen\/nlx042","article-title":"Multiplex detection of pediatric low-grade glioma signature fusion transcripts and duplications using the NanoString nCounter system","volume":"76","author":"Ryall","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1038\/s41379-018-0050-6","article-title":"Duplications of KIAA1549 and BRAF screening by Droplet Digital PCR from formalin-fixed paraffin-embedded DNA is an accurate alternative for KIAA1549-BRAF fusion detection in pilocytic astrocytomas","volume":"31","author":"Appay","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1080\/08880018.2019.1679304","article-title":"Rapid fully-automated assay for routine molecular diagnosis of BRAF mutations for personalized therapy of low grade gliomas","volume":"37","author":"Merlin","year":"2020","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.critrevonc.2018.03.027","article-title":"The identification and isolation of CTCs: A biological Rubik\u2019s cube","volume":"126","author":"Mansilla","year":"2018","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bonner, E.R., Bornhorst, M., Packer, R.J., and Nazarian, J. (2018). Liquid biopsy for pediatric central nervous system tumors. NPJ Precis. Oncol., 2.","DOI":"10.1038\/s41698-018-0072-z"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Romero, N., Carri\u00f3n-Navarro, J., Areal-Hidalgo, P., Ortiz de Mendivil, A., Asensi-Puig, A., Madurga, R., N\u00fa\u00f1ez-Torres, R., Gonz\u00e1lez-Neira, A., Belda-Iniesta, C., and Gonz\u00e1lez-Rumayor, V. (2020). BRAF V600E Detection in Liquid Biopsies from Pediatric Central Nervous System Tumors. Cancers, 12.","DOI":"10.3390\/cancers12010066"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1093\/neuonc\/nos077","article-title":"Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas","volume":"14","author":"Horbinski","year":"2012","journal-title":"Neuro-Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1111\/nan.12013","article-title":"Outcome analysis of childhood pilocytic astrocytomas: A retrospective study of 148 cases at a single institution","volume":"39","author":"Colin","year":"2013","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_52","first-page":"3718","article-title":"BRAF mutation is associated with an improved survival in glioma\u2014a systematic review and meta-analysis","volume":"55","author":"Vuong","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1200\/JCO.2014.58.3922","article-title":"BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma","volume":"33","author":"Mistry","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Workman, J.L., and Abmayr, S.M. (2014). Fundamentals of Chromatin, Springer.","DOI":"10.1007\/978-1-4614-8624-4"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Crabtree, J.S. (2020). Fundamentals of epigenetics. Clinical Precision Medicine, Elsevier.","DOI":"10.1016\/B978-0-12-819834-6.00003-3"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"37112","DOI":"10.18632\/oncotarget.26430","article-title":"Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes","volume":"9","author":"Huang","year":"2018","journal-title":"Oncotarget"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s40495-018-0141-6","article-title":"Histone H3 mutations in cancer","volume":"4","author":"Wan","year":"2018","journal-title":"Curr. Pharmacol. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1007\/s00401-014-1337-4","article-title":"Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas","volume":"128","author":"Bechet","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s00401-012-0998-0","article-title":"K27M mutation in histone H3. 3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas","volume":"124","author":"Buczkowicz","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Nikbakht, H., Panditharatna, E., Mikael, L.G., Li, R., Gayden, T., Osmond, M., Ho, C.-Y., Kambhampati, M., Hwang, E.I., and Faury, D. (2016). Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nat. Commun., 7.","DOI":"10.1038\/ncomms11185"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/bpa.12768","article-title":"Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant","volume":"30","author":"Dufour","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Stallard, S., Savelieff, M.G., Wierzbicki, K., Mullan, B., Miklja, Z., Bruzek, A., Garcia, T., Siada, R., Anderson, B., and Singer, B.H. (2018). CSF H3F3A K27M circulating tumor DNA copy number quantifies tumor growth and in vitro treatment response. Acta Neuropathol. Commun., 6.","DOI":"10.1186\/s40478-018-0580-7"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40478-017-0436-6","article-title":"Detection of Histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma","volume":"5","author":"Huang","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s00401-018-1936-6","article-title":"Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA","volume":"137","author":"Pan","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5850","DOI":"10.1158\/1078-0432.CCR-18-1345","article-title":"Clinically relevant and minimally invasive tumor surveillance of pediatric diffuse midline gliomas using patient-derived liquid biopsy","volume":"24","author":"Panditharatna","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.cca.2013.05.022","article-title":"Circulating cell free DNA: Preanalytical considerations","volume":"424","author":"Rolet","year":"2013","journal-title":"Clin. Chim. Acta"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s00401-015-1478-0","article-title":"Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes","volume":"130","author":"Castel","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Sareen, H., Garrett, C., Lynch, D., Powter, B., Brungs, D., Cooper, A., Po, J., Koh, E.-S., Vessey, J.Y., and McKechnie, S. (2020). The role of liquid biopsies in detecting molecular tumor biomarkers in brain cancer patients. Cancers, 12.","DOI":"10.3390\/cancers12071831"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"224ra24","DOI":"10.1126\/scitranslmed.3007094","article-title":"Detection of circulating tumor DNA in early-and late-stage human malignancies","volume":"6","author":"Bettegowda","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1227\/NEU.0b013e318214a66e","article-title":"Primary neurosurgery for pediatric low-grade gliomas: A prospective multi-institutional study from the Children\u2019s Oncology Group","volume":"68","author":"Wisoff","year":"2011","journal-title":"Neurosurgery"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7303","DOI":"10.1158\/1078-0432.CCR-19-2177","article-title":"Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation\u2013positive relapsed or refractory low-grade glioma: Results from a phase I\/IIa study","volume":"25","author":"Hargrave","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1002\/pbc.24958","article-title":"Long-term outcome of 4040 children diagnosed with pediatric low-grade gliomas: An analysis of the Surveillance Epidemiology and End Results (SEER) database","volume":"61","author":"Bandopadhayay","year":"2014","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1007\/s11912-014-0398-9","article-title":"Advances in the management of low-grade gliomas","volume":"16","author":"Rao","year":"2014","journal-title":"Curr. Oncol. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"747","DOI":"10.3171\/jns.1997.86.5.0747","article-title":"Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas","volume":"86","author":"Packer","year":"1997","journal-title":"J. Neurosurg."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e366","DOI":"10.1097\/MPH.0000000000000142","article-title":"Outcomes of pediatric low-grade gliomas treated with radiation therapy: A single-institution study","volume":"36","author":"Raikar","year":"2014","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3691","DOI":"10.1200\/JCO.2008.21.2738","article-title":"Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: Prospective evaluation of cognitive, endocrine, and hearing deficits","volume":"27","author":"Merchant","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.semradonc.2009.09.005","article-title":"Brain tumors across the age spectrum: Biology, therapy, and late effects","volume":"20","author":"Merchant","year":"2010","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/S1470-2045(17)30679-4","article-title":"Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: An open-label, phase 2 trial","volume":"18","author":"Planchard","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1200\/JCO.2017.73.6785","article-title":"Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600\u2013mutant anaplastic thyroid cancer","volume":"36","author":"Subbiah","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1056\/NEJMoa1412690","article-title":"Improved overall survival in melanoma with combined dabrafenib and trametinib","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa1708539","article-title":"Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma","volume":"377","author":"Long","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_82","first-page":"LBA19_PR","article-title":"The first study of dabrafenib in pediatric patients with BRAF V600\u2013mutant relapsed or refractory low-grade gliomas","volume":"27","author":"Hargrave","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"526","DOI":"10.3389\/fonc.2018.00526","article-title":"BRAF V600E inhibitor (Vemurafenib) for BRAF V600E mutated low grade gliomas","volume":"8","author":"Ceglie","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Robinson, G.W., Orr, B.A., and Gajjar, A. (2014). Complete clinical regression of a BRAF V600E-mutant pediatric glioblastoma multiforme after BRAF inhibitor therapy. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-258"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s11060-019-03271-3","article-title":"Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201","volume":"145","author":"Chi","year":"2019","journal-title":"J. Neuro-Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1093\/neuonc\/noq191","article-title":"Temozolomide in the treatment of high-grade gliomas in children: A report from the Children\u2019s Oncology Group","volume":"13","author":"Cohen","year":"2011","journal-title":"Neuro-Oncol."},{"key":"ref_87","first-page":"153","article-title":"Pediatric high-grade glioma: Biologically and clinically in need of new thinking","volume":"19","author":"Jones","year":"2017","journal-title":"Neuro-Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.molonc.2012.09.003","article-title":"HDAC inhibitor-based therapies: Can we interpret the code?","volume":"6","author":"New","year":"2012","journal-title":"Mol. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.2147\/OTT.S30773","article-title":"Profile of panobinostat and its potential for treatment in solid tumors: An update","volume":"6","author":"Anne","year":"2013","journal-title":"Oncotargets Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nm.3855","article-title":"Functionally defined therapeutic targets in diffuse intrinsic pontine glioma","volume":"21","author":"Grasso","year":"2015","journal-title":"Nat. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1158\/0008-5472.CAN-14-2356","article-title":"Genetic and pharmacological screens converge in identifying FLIP, BCL2, and IAP proteins as key regulators of sensitivity to the TRAIL-inducing anticancer agent ONC201\/TIC10","volume":"75","author":"Allen","year":"2015","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"117ra17","DOI":"10.1126\/scitranslmed.3004828","article-title":"Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects","volume":"5","author":"Allen","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"882","DOI":"10.18632\/oncotarget.1801","article-title":"Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma","volume":"5","author":"Li","year":"2014","journal-title":"Oncotarget"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1093\/neuonc\/nox210","article-title":"Monoamines in glioblastoma: Complex biology with therapeutic potential","volume":"20","author":"Caragher","year":"2018","journal-title":"Neuro-Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"5392","DOI":"10.1158\/1078-0432.CCR-18-1040","article-title":"Metabolic reprogramming by dual AKT\/ERK inhibition through imipridones elicits unique vulnerabilities in glioblastoma","volume":"24","author":"Ishida","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"ra18","DOI":"10.1126\/scisignal.aac4374","article-title":"ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2\u03b1 kinases","volume":"9","author":"Kline","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/s41571-019-0177-5","article-title":"Challenges to curing primary brain tumours","volume":"16","author":"Aldape","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/aps.2016.167","article-title":"Insights into molecular therapy of glioma: Current challenges and next generation blueprint","volume":"38","author":"Rajesh","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"551","DOI":"10.18632\/oncotarget.26560","article-title":"Sustained response of three pediatric BRAFV600E mutated high-grade gliomas to combined BRAF and MEK inhibitor therapy","volume":"10","author":"Toll","year":"2019","journal-title":"Oncotarget"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/nature10662","article-title":"RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF (V600E)","volume":"480","author":"Poulikakos","year":"2011","journal-title":"Nature"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"387","DOI":"10.21037\/atm.2017.06.09","article-title":"Overcoming resistance to BRAF inhibitors","volume":"5","author":"Arozarena","year":"2017","journal-title":"Ann. Transl. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"7294","DOI":"10.1158\/1078-0432.CCR-17-3572","article-title":"A phase I and pharmacokinetic study of oral dabrafenib in children and adolescent patients with recurrent or refractory BRAF V600 mutation\u2013positive solid tumors","volume":"25","author":"Kieran","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/annonc\/mdy273.395","article-title":"407TiP Phase II open-label, global study evaluating dabrafenib in combination with trametinib in pediatric patients with BRAF V600\u2013mutant high-grade glioma (HGG) or low-grade glioma (LGG)","volume":"29","author":"Hargrave","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e26969","DOI":"10.1002\/pbc.26969","article-title":"Response to the BRAF\/MEK inhibitors dabrafenib\/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib","volume":"65","author":"Marks","year":"2018","journal-title":"Pediatr. Blood Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/607\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:19:48Z","timestamp":1760159988000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,4]]},"references-count":104,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["cancers13040607"],"URL":"https:\/\/doi.org\/10.3390\/cancers13040607","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,4]]}}}