K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas

Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3....

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Vydáno v:	Acta neuropathologica Ročník 124; číslo 3; s. 439 - 447
Hlavní autoři:	Khuong-Quang, Dong-Anh, Buczkowicz, Pawel, Rakopoulos, Patricia, Liu, Xiao-Yang, Fontebasso, Adam M., Bouffet, Eric, Bartels, Ute, Albrecht, Steffen, Schwartzentruber, Jeremy, Letourneau, Louis, Bourgey, Mathieu, Bourque, Guillaume, Montpetit, Alexandre, Bourret, Genevieve, Lepage, Pierre, Fleming, Adam, Lichter, Peter, Kool, Marcel, von Deimling, Andreas, Sturm, Dominik, Korshunov, Andrey, Faury, Damien, Jones, David T., Majewski, Jacek, Pfister, Stefan M., Jabado, Nada, Hawkins, Cynthia
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Berlin/Heidelberg Springer-Verlag 01.09.2012 Springer Springer Nature B.V
Témata:	Adolescent Algorithms Biopsy Brain cancer Brain research Brain stem Brain Stem Neoplasms - genetics Brain Stem Neoplasms - mortality Brain Stem Neoplasms - pathology Brain tumors Cancer research Cancer therapies Child Child, Preschool Children Clinical trials Comparative analysis copy number Cortex Decision making Female Gene Expression Profiling Genetic aspects Glioblastoma Glioma Glioma - genetics Glioma - mortality Glioma - pathology Gliomas Histones Histones - genetics Hospitals Humans Infant Kinases Male Medical research Medicine Medicine & Public Health Mutation Myc protein Neurosciences Original Paper p53 protein Pathology Pediatrics Platelet-derived growth factor Pons - pathology Prognosis Survival Survival Rate Tumor proteins Tumors Canada Montreal Quebec Canada Germany H3.3 DIPG Targeted therapy TP53 Survival ATRX
ISSN:	0001-6322, 1432-0533, 1432-0533
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Shrnutí:	Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B , IDH , ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children ( p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.
Bibliografie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	0001-6322 1432-0533 1432-0533
DOI:	10.1007/s00401-012-0998-0