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

By Jinghui Zhang, Gang Wu, Claudia P. Miller, R. Tatevossian, J. Dalton, Bo Tang, Wilda Orisme, C. Punchihewa, Matthew Parker, I. Qaddoumi and 38 more. Nature Genetics, 2013

736 citations recorded by the source corpus.

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.

Subfields: Genetics, Neurology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/b43acfe563e92a0c3fa4660b068f2e9c4ff9370c

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In Genetics

1. H. Ohgaki
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4. R. Jenkins
5. McKinsey L. Goodenberger

In Pulmonary and Respiratory Medicine

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Citations in the corpus

• Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours (2014, background): “FGFR1 fusions, although not recurrent, have been observed in lung squamous cell carcinoma (LUSC), breast cancer, GBM, and low-grade brain tumours [13,32,33].”
• Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas (2015, neutral): “Headache 64/252 (25) 15/72 (21) 39/129 (30) 10/51 (20)”
• The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary (2016, background): “Information on the distinct underlying genetic abnormalities in pediatric diffuse gliomas is beginning to allow the separation of some entities from histologically similar adult counterparts [24, 37, 52].”