Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

David Ellison and colleagues report whole-genome sequencing of pediatric low-grade gliomas, the most common pediatric brain tumor. They identify a range of genomic alterations, including recurrent and mutually exclusive duplications of the FGFR1 region encoding the tyrosine kinase domain and rearran...

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Bibliographic Details
Published in:	Nature genetics Vol. 45; no. 6; pp. 602 - 612
Main Authors:	Zhang, Jinghui, Wu, Gang, Miller, Claudia P, Tatevossian, Ruth G, Dalton, James D, Tang, Bo, Orisme, Wilda, Punchihewa, Chandanamali, Parker, Matthew, Qaddoumi, Ibrahim, Boop, Fredrick A, Lu, Charles, Kandoth, Cyriac, Ding, Li, Lee, Ryan, Huether, Robert, Chen, Xiang, Hedlund, Erin, Nagahawatte, Panduka, Rusch, Michael, Boggs, Kristy, Cheng, Jinjun, Becksfort, Jared, Ma, Jing, Song, Guangchun, Li, Yongjin, Wei, Lei, Wang, Jianmin, Shurtleff, Sheila, Easton, John, Zhao, David, Fulton, Robert S, Fulton, Lucinda L, Dooling, David J, Vadodaria, Bhavin, Mulder, Heather L, Tang, Chunlao, Ochoa, Kerri, Mullighan, Charles G, Gajjar, Amar, Kriwacki, Richard, Sheer, Denise, Gilbertson, Richard J, Mardis, Elaine R, Wilson, Richard K, Downing, James R, Baker, Suzanne J, Ellison, David W
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.06.2013 Nature Publishing Group
Subjects:	692/308/2056 Adolescent Agriculture Animal Genetics and Genomics Animals Base Sequence Biomedicine Brain Neoplasms - genetics Brain Neoplasms - pathology Brain tumors Cancer Research Child Child, Preschool Children & youth Diagnosis DNA sequencing Female Gene Duplication Gene expression Gene Function Gene Rearrangement Genes, myb Genetic aspects Genome-Wide Association Study Genomes Glioma - genetics Glioma - pathology Gliomas Human Genetics Humans Infant Kinases Male Mice Mice, Nude Molecular Sequence Data Morbidity Mortality Mutation Neoplasm Grading Neoplasm Transplantation Nucleotide sequencing Pediatrics Proteins Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins B-raf Receptor, Fibroblast Growth Factor, Type 1 - genetics Risk factors Sequence Analysis, DNA Signal Transduction Trans-Activators - genetics Transcriptome Tumors United States
ISSN:	1061-4036, 1546-1718, 1546-1718
Online Access:	Get full text
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Summary:	David Ellison and colleagues report whole-genome sequencing of pediatric low-grade gliomas, the most common pediatric brain tumor. They identify a range of genomic alterations, including recurrent and mutually exclusive duplications of the FGFR1 region encoding the tyrosine kinase domain and rearrangements of MYB . The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF , RAF1 , FGFR1 , MYB , MYBL1 and genes with histone-related functions, including H3F3A and ATRX , in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53 -null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs.
Bibliography:	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:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/ng.2611