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

Gang Wu, Alexander K. Diaz, Barbara S. Paugh, Sherri L. Rankin, Bensheng Ju, Yongjin Li, Xiaoyan Zhu, Chunxu Qu, Xiang Chen, Junyuan Zhang, John Easton, Michael Edmonson, Xiaotu Ma, Charles Lu, Panduka Nagahawatte, Erin Hedlund, Michael Rusch, Stanley Pounds, Tong Lin, Arzu Onar-ThomasRobert Huether, Richard Kriwacki, Matthew Parker, Pankaj Gupta, Jared Becksfort, Lei Wei, Heather L. Mulder, Kristy Boggs, Bhavin Vadodaria, Donald Yergeau, Jake C. Russell, Kerri Ochoa, Robert Fulton, Lucinda L. Fulton, Chris Jones, Frederick A. Boop, Alberto Broniscer, Cynthia Wetmore, Amar Gajjar, Li Ding, Elaine R. Mardis, Richard K. Wilson, Michael R. Taylor, James R. Downing, David W. Ellison, Jinghui Zhang, Suzanne J. Baker

Research output: Contribution to journalArticle

462 Scopus citations

Abstract

Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. 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. 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.

Original languageEnglish
Pages (from-to)444-450
Number of pages7
JournalNature Genetics
Volume46
Issue number5
DOIs
StatePublished - May 2014

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    Wu, G., Diaz, A. K., Paugh, B. S., Rankin, S. L., Ju, B., Li, Y., Zhu, X., Qu, C., Chen, X., Zhang, J., Easton, J., Edmonson, M., Ma, X., Lu, C., Nagahawatte, P., Hedlund, E., Rusch, M., Pounds, S., Lin, T., ... Baker, S. J. (2014). The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics, 46(5), 444-450. https://doi.org/10.1038/ng.2938