title: BRAF alterations in primary glial and glioneuronal neoplasms of the central nervous system with identification of 2 novel KIAA1549:BRAF fusion variants.
abstract: Recent studies highlight the importance of BRAF alterations resulting in mitogen activated protein kinase (MAK/ERK) pathway activation in low-grade CNS tumors. We studied 106 low-grade CNS neoplasms in a cohort of primarily pediatric patients to identify the prevalence and clinicopathologic significance of these alterations. Polymerase chain reaction testing identified KIAA1549:BRAF fusions in 51 (48%) tumors overall, including 42 (60%) pilocytic astrocytomas, 4 (17%) unclassifiable low-grade gliomas, 4 (36%) low-grade glioneuronal/neuroepithelial tumors, 0 (of 5) pleomorphic xanthoastrocytomas, 0 (of 4) diffuse astrocytomas (World Health Organization grade II), and 1 (of 3, 33%) pilomyxoid astrocytoma. KIAA1549:BRAF gene fusions confirmed by sequencing included the previously reported ones involving exons 1-16/9-18 (49%), 1-15/9-18 (35%), and 1-16/11-18 (8%) and 2 fusions with novel breakpoints: 1-15/11-18 (6%) and 1-17/10-18 (1%). DNA sequencing identified BRAF mutations in 8% of tumors. BRAF mutations were absent. KIAA1549:BRAF fusions were significantly more frequent in infratentorial (57%) and optic pathway (59%) tumors versus supratentorial (19%) tumors (p = 0.001). We did not identify significantly improved progression-free survival in tumors with fusions. In summary, KIAA1549:BRAF fusions predominate in pilocytic astrocytomas but are also present in some low-grade unclassifiable gliomas and glioneuronal tumors. The prognostic and therapeutic significance of this alteration is unclear and merits further study.
authors.affiliation: Division of Neuropathology, Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Lin
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Karajannis
authors.forename: Susan C
authors.initials: SC
authors.lastname: Williams
authors.forename: Genevieve
authors.initials: G
authors.lastname: Legault
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.forename: Peter C
authors.initials: PC
authors.lastname: Burger
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Allen
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Eli E
authors.initials: EE
authors.lastname: Bar
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D005910:Glioma / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000473:pathology; D017354:Point Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D011993:Recombinant Fusion Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf