The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

Suzanne Baker, Jinghui Zhang and colleagues report the identification of recurrent somatic mutations in the bone morphogenetic protein (BMP) receptor ACVR1 in 32% of diffuse intrinsic pontine gliomas. Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 yea...

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Published in:Nature genetics Vol. 46; no. 5; pp. 444 - 450
Main Authors: Wu, Gang, Diaz, Alexander K, Paugh, Barbara S, Rankin, Sherri L, Ju, Bensheng, Li, Yongjin, Zhu, Xiaoyan, Qu, Chunxu, Chen, Xiang, Zhang, Junyuan, Easton, John, Edmonson, Michael, Ma, Xiaotu, Lu, Charles, Nagahawatte, Panduka, Hedlund, Erin, Rusch, Michael, Pounds, Stanley, Lin, Tong, Onar-Thomas, Arzu, Huether, Robert, Kriwacki, Richard, Parker, Matthew, Gupta, Pankaj, Becksfort, Jared, Wei, Lei, Mulder, Heather L, Boggs, Kristy, Vadodaria, Bhavin, Yergeau, Donald, Russell, Jake C, Ochoa, Kerri, Fulton, Robert S, Fulton, Lucinda L, Jones, Chris, Boop, Frederick A, Broniscer, Alberto, Wetmore, Cynthia, Gajjar, Amar, Ding, Li, Mardis, Elaine R, Wilson, Richard K, Taylor, Michael R, Downing, James R, Ellison, David W, Zhang, Jinghui, Baker, Suzanne J
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.05.2014
Nature Publishing Group
Subjects:
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Activin Receptors, Type I - genetics
Age
Agriculture
Animal Genetics and Genomics
Animals
Bioinformatics
Biomedicine
Brain Stem Neoplasms - genetics
Cancer
Cancer Research
Child
Children & youth
Cohort Studies
Computational Biology
Gene Expression Profiling
Gene Function
Gene Fusion - genetics
Genes
Genetic aspects
Genetic research
Genomes
Genomics
Glioma - genetics
Gliomas
Human Genetics
Humans
Immunoblotting
Immunohistochemistry
Kinases
letter
Medical prognosis
Microarray Analysis
Mutation
Pediatrics
Receptor, trkA - genetics
Receptor, trkB - genetics
Receptor, trkC - genetics
Reverse Transcriptase Polymerase Chain Reaction
Sequence Analysis, DNA
Signal Transduction - genetics
Statistics, Nonparametric
Survival
Tumors
Tumors in children
Zebrafish
ISSN:1061-4036, 1546-1718, 1546-1718
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Summary:Suzanne Baker, Jinghui Zhang and colleagues report the identification of recurrent somatic mutations in the bone morphogenetic protein (BMP) receptor ACVR1 in 32% of diffuse intrinsic pontine gliomas. Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis 1 . We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX , in both DIPGs and NBS-HGGs 2 , 3 , 4 , 5 . Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase–RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.
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ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/ng.2938