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

Abstract

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.

• Authors: Jinghui Zhang, Gang Wu, Claudia P Miller, Ruth G Tatevossian, James D Dalton, Bo Tang, Wilda Orisme, Chandanamali Punchihewa, Matthew Parker, Ibrahim Qaddoumi, Fredrick A Boop, Charles Lu, Cyriac Kandoth, Li Ding, Ryan Lee, Robert Huether, Xiang Chen, Erin Hedlund, Panduka Nagahawatte, Michael Rusch, Kristy Boggs, Jinjun Cheng, Jared Becksfort, Jing Ma, Guangchun Song, Yongjin Li, Lei Wei, Jianmin Wang, Sheila Shurtleff, John Easton, David Zhao, Robert S Fulton, Lucinda L Fulton, David J Dooling, Bhavin Vadodaria, Heather L Mulder, Chunlao Tang, Kerri Ochoa, Charles G Mullighan, Amar Gajjar, Richard Kriwacki, Denise Sheer, Richard J Gilbertson, Elaine R Mardis, Richard K Wilson, James R Downing, Suzanne J Baker, David W Ellison, St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
• Journal: Nature genetics (Nat Genet) Vol. 45 Issue 6 Pg. 602-12 (Jun 2013) ISSN: 1546-1718 [Electronic] United States
• PMID: 23583981 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MYBL1 protein, human
• Proto-Oncogene Proteins
• Trans-Activators
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1
• BRAF protein, human
• Proto-Oncogene Proteins B-raf

Topics

• Adolescent
• Animals
• Base Sequence
• Brain Neoplasms (genetics, pathology)
• Child
• Child, Preschool
• Female
• Gene Duplication
• Gene Rearrangement
• Genes, myb
• Genome-Wide Association Study
• Glioma (genetics, pathology)
• Humans
• Infant
• Male
• Mice
• Mice, Nude
• Molecular Sequence Data
• Mutation
• Neoplasm Grading
• Neoplasm Transplantation
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins B-raf
• Receptor, Fibroblast Growth Factor, Type 1 (genetics)
• Sequence Analysis, DNA
• Signal Transduction
• Trans-Activators (genetics)
• Transcriptome