title: Genetic Analysis of Diffuse High-Grade Astrocytomas in Infancy Defines a Novel Molecular Entity.
abstract: Pediatric high-grade gliomas are considered to be different when compared to adult high-grade gliomas in their pathogenesis and biological behavior. Recently, common genetic alterations, including mutations in the H3F3A/ATRX/DAXX pathway, have been described in approximately 30% of the pediatric cases. However, only few cases of infant high-grade gliomas have been analyzed so far. We investigated the molecular features of 35 infants with diffuse high-grade astrocytomas, including 8 anaplastic astrocytomas [World Health Organization (WHO) grade III] and 27 glioblastomas (WHO grade IV) by immunohistochemistry, multiplex ligation probe-dependent amplification (MLPA), pyrosequencing of glioma-associated genes and molecular inversion probe (MIP) assay. MIP and MLPA analyses showed that chromosomal alterations are significantly less frequent in infants compared with high-grade gliomas in older children and adults. We only identified H3F3A K27M in 2 of 34 cases (5.9%), with both tumors located in the posterior fossa. PDGFRA amplifications were absent, and CDKN2A loss could be observed only in two cases. Conversely, 1q gain (22.7%) and 6q loss (18.2%) were identified in a subgroup of tumors. Loss of SNORD located on chromosome 14q32 was observed in 27.3% of the infant tumors, a focal copy number change not previously described in gliomas. Our findings indicate that infant high-grade gliomas appear to represent a distinct genetic entity suggesting a different pathogenesis and biological behavior.
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Gerrit H
authors.initials: GH
authors.lastname: Gielen
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Gessi
authors.affiliation: Department of Neurology and Psychiatry, University of Rome "La Sapienza", Pozzilli, Italy.
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Buttarelli
authors.affiliation: Department of Neurology and Psychiatry, University of Rome "La Sapienza", Pozzilli, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Baldi
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hammes
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: zur Muehlen
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Doerner
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Dorota
authors.initials: D
authors.lastname: Denkhaus
authors.affiliation: Department of Neuroradiology, University of Würzburg, Würzburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Warmuth-Metz
authors.affiliation: Department of Radiological, Oncological and Anatomo-Pathological Sciences, University of Rome "La Sapienza", Pozzilli, Italy.|IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Felice
authors.initials: F
authors.lastname: Giangaspero
authors.affiliation: Department of Pathology, Catholic University, Rome, Italy.
authors.forename: Libero
authors.initials: L
authors.lastname: Lauriola
authors.affiliation: Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: André O
authors.initials: AO
authors.lastname: von Bueren
authors.affiliation: Division of Paediatric Haematology and Oncology, Department of Paediatrics and Adolescent Medicine, University Medical Center Goettingen, Goettingen, Germany.
authors.forename: Christof M
authors.initials: CM
authors.lastname: Kramm
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Waha
authors.affiliation: Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Pietsch
mesh_terms: D000293:Adolescent; D001254:Astrocytoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004265:DNA Helicases / Q000378:metabolism; D005260:Female; D006657:Histones / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D009687:Nuclear Proteins; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: ALT; ATRX; H3F3A; SNORD; glioblastoma; high-grade glioma; infants; molecular inversion probe analysis; multiplex ligation probe-dependent amplification; pediatric brain tumors