• Prerana Jha, Irene Rosita Pia Patric, Sudhanshu Shukla, Pankaj Pathak, Jagriti Pal, Vikas Sharma, Sivaarumugam Thinagararanjan, Vani Santosh, Vaishali Suri, Mehar Chand Sharma, Arimappamagan Arivazhagan, A... more shish Suri, Deepak Gupta, Kumaravel Somasundaram, and Chitra Sarkar. less
• Department of Pathology, All India Institute of Medical Sciences, New Delhi, India (P.J., P.P., VI.S., VA.S., M.C.S., C.S.); Department of Microbiology and Cell Biology, Indian Institute of Science, Bangal... more ore, India (I.R.P.P., S.S., J.P., S.T., K.S.); Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India (VAI.S.); Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bangalore, India (A.A.); Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India (A.S., D.G.). less
• Neuro-oncology. 2014 Dec 1; 16 (12): 1607-17.

BackgroundPediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH)1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways.MethodsGenome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done.ResultsDistinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine-phosphate-guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment.ConclusionsOur study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation-specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation.© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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