title: Gliomatosis cerebri in children shares molecular characteristics with other pediatric gliomas.
abstract: Gliomatosis cerebri (GC), a rare and deadly CNS neoplasm characterized by involvement of at least three cerebral lobes, predominantly affects adults. While a few small series have reported its occurrence in children, little is known about the molecular characteristics of pediatric GC. We reviewed clinical, radiological, and histological features of pediatric patients with primary GC treated at our institution over 15 years. Targeted sequencing of mutational hotspots in H3F3A, IDH1/2, and BRAF, and genome-wide analysis of DNA methylation and copy number abnormalities was performed in available tumors. Thirty-two patients [23 (72 %) with type 1 and 9 (28 %) with type 2 GC] were identified. Median age at diagnosis was 10.2 years (range 1.5-19.1). A median of 4 cerebral lobes (range 3-8) was affected at diagnosis. In addition, symmetrical bithalamic involvement was observed in 9 (28 %) patients. Twenty-two patients (69 %) had an anaplastic astrocytoma. Despite aggressive therapy, only two patients younger than 3 years at diagnosis are long-term survivors. Clustering analysis of methylation array data from 18 cases classified tumors as IDH (n = 3, 17 %), G34 (n = 4, 22 %), mesenchymal (n = 3, 17 %), and RTK I 'PDGFRA' (n = 8, 44 %). No tumors were classified as K27 subgroup. PDGFRA was the most commonly amplified oncogene in 4 of 22 tumors (18 %). H3F3A p.G34 occurred in all cases classified as G34. Two of 3 cases in the IDH subgroup had IDH1 p.R132H. No H3F3A p.K27 M, IDH2 p.R172, or BRAF p.V600E mutations were observed. There was a trend towards improved survival in the IDH subgroup (P = 0.056). Patients with bithalamic involvement had worse outcomes (P = 0.019). Despite some overlap, the molecular features of pediatric GC are distinct from its adult counterpart. Like in adults, the similarity of genetic and epigenetic characteristics with other infiltrative high-grade gliomas suggests that pediatric GC does not represent a distinct molecular entity.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA. alberto.broniscer@stjude.org.|Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Memphis, TN, 38103, USA. alberto.broniscer@stjude.org.
authors.forename: Alberto
authors.identifier: http://orcid.org/0000-0001-9646-0463
authors.initials: A
authors.lastname: Broniscer
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Chamdine
authors.affiliation: Department of Diagnostic Imaging, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Hwang
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar-Thomas
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shurtleff
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Sariah
authors.initials: S
authors.lastname: Allen
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.|Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Memphis, TN, 38103, USA.
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Northcott
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Orr
mesh_terms: D000293:Adolescent; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D018302:Neoplasms, Neuroepithelial / Q000145:classification / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D012189:Retrospective Studies; D016019:Survival Analysis; D055815:Young Adult
keywords: Children; DNA methylation profiles; Gliomatosis cerebri; Molecular classification