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.

DOI: 10.1038/ng.2611

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@inproceedings{Zhang2013WholegenomeSI, title={Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas}, author={Jinghui Zhang and Gang Wu and Claudia P. Miller and Ruth G. Tatevossian and James D. Dalton and Bo Tang and Wilda Orisme and Chandanamali Punchihewa and Matthew Parker and Ibrahim Qaddoumi and Fredrick A. Boop and Charles Lu and Cyriac Kandoth and Li Ding and Ryan Lee and Robert Huether and Xiang Chen and Erin Hedlund and Panduka Nagahawatte and Michael Rusch and Kristy Boggs and Jinjun Cheng and Jared Becksfort and Jing Ma and Guangchun Song and Yongjin Li and Lei Wei and Jianmin Wang and Sheila Shurtleff and John Easton and David Zhao and Robert S. Fulton and Lucinda L. Fulton and David J. Dooling and Bhavin Vadodaria and Heather L. Mulder and Chunlao Tang and Kerri Ochoa and Charles G. Mullighan and Amar Gajjar and Richard Kriwacki and Denise Sheer and Richard J. Gilbertson and Elaine R. Mardis and Richard K. Wilson and James R. Downing and Suzanne J. Baker and David W. Ellison}, booktitle={Nature genetics}, year={2013} }