title: Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM.
abstract: Mutations in H3.3-ATRX-DAXX chromatin remodeling pathway have been reported in pediatric GBMs. H3.3 (H3F3A) mutations may affect transcriptional regulation by altered global histone-methylation. Therefore, we analyzed yet partly understood global histone code (H3K-4/9/27/36) trimethylation pattern in H3F3A-ATRX mutants and wild-type. H3F3A, HIST1H3B, IDH1, ATRX, DAXX and Tp53 mutations were identified by sequencing/immunohistochemistry in 27 pediatric GBMs. Global histone-methylation H3K-4/9/27/36me3 and Polycomb-protein EZH2 expression were evaluated by immunohistochemistry. H3F3A-ATRX mutation was observed in 66.7 % (18/27) of pediatric GBMs. K27M and G34R-H3F3A mutations were found in 37 % (10/27) and 14.8 % (4/27) patients respectively. G34V-H3F3A, HIST1H3B and IDH1 mutations were absent. Notably, commonest global histone-methylation mark lost was H3K27me3 (17/25, 68 %) followed by H3K4me3 (45.5 %, 10/22) and H3K9me3 (18.2 %, 4/22). Global H3K36me3 showed no loss. Most significant observation was loss of one or more histone-trimethylation mark in 80 % (20/25) pediatric GBMs. Notably, simultaneous loss of H3K27me3 and H3K4me3 were present in 7/22 (31.8 %) of pediatric GBMs. Low expression of EZH2 was found in 12/24 (50 %) of cases. However no significant correlation of loss of histone-marks or EZH2 expression with H3F3A-ATRX mutants (loss of at least one histone-marks in 87.5 % (14/16) cases) versus wild-types (loss of at least one histone-marks in 75 % (6/8) cases) was seen. The present study highlights for the first time combinatorial loss of one or more histone-trimethylation marks associated with majority of pediatric GBMs and the finding suggests significant role of histone-code in the molecular biology that underlies pediatric GBMs. Hence therapies for patients with particular combinations of histone modifications present opportunity to design innovative patient-tailored treatment protocols.
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Pathak
authors.forename: Prerana
authors.initials: P
authors.lastname: Jha
authors.forename: Suvendu
authors.initials: S
authors.lastname: Purkait
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.forename: Vaishali
authors.initials: V
authors.lastname: Suri
authors.forename: Mehar C
authors.initials: MC
authors.lastname: Sharma
authors.forename: Mohammed
authors.initials: M
authors.lastname: Faruq
authors.forename: Ashish
authors.initials: A
authors.lastname: Suri
authors.forename: Chitra
authors.initials: C
authors.lastname: Sarkar
mesh_terms: D002648:Child; D004265:DNA Helicases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005909:Glioblastoma / Q000235:genetics*; D006657:Histones / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D012189:Retrospective Studies; D000075924:X-linked Nuclear Protein
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein