Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1
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Date
2013
Author(s)
Ramkissoon, Lori
Horowitz, Peleg
Craig, Justin
Ramkissoon, Shakti
Rich, Benjamin
Schumacher, Steven
McKenna, Aaron
Lawrence, Michael
Bergthold, Guillaume
Brastianos, Priscilla
Tabak, Barbara
Ducar, Matthew
Van Hummelen, Paul
MacConaill, Laura
Pouissant-Young, Tina
Cho, Yoon-Jae
Taha, Hala
Mahmoud, Madeha
Bowers, Daniel
Margraf, Linda
Tabori, Uri
Hawkins, Cynthia
Packer, Roger
Hill, D. Ashley
Pomeroy, Scott
Eberhart, Charles
Dunn, Ian
Goumnerova, Liliana
Getz, Gad
Chan, Jennifer
Santagata, Sandro
Hahn, William
Stiles, Charles
Ligon, Azra
Kieran, Mark
Beroukhim, Rameen
Ligon, Keith
Publisher
National Academy of Sciences
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Citation
Ramkissoon, L. A., P. M. Horowitz, J. M. Craig, S. H. Ramkissoon, B. E. Rich, S. E. Schumacher, A. McKenna, et al. 2013. “Genomic Analysis of Diffuse Pediatric Low-Grade Gliomas Identifies Recurrent Oncogenic Truncating Rearrangements in the Transcription Factor MYBL1.” Proceedings of the National Academy of Sciences 110 (20): 8188–93. https://doi.org/10.1073/pnas.1300252110.
Abstract
Pediatric low-grade gliomas (PLGGs) are among the most common solid tumors in children but, apart from BRAF kinase mutations or duplications in specific subclasses, few genetic driver events are known. Diffuse PLGGs comprise a set of uncommon subtypes that exhibit invasive growth and are therefore especially challenging clinically. We performed high-resolution copy-number analysis on 44 formalin-fixed, paraffin-embedded diffuse PLGGs to identify recurrent alterations. Diffuse PLGGs exhibited fewer such alterations than adult low-grade gliomas, but we identified several significantly recurrent events. The most significant event, 8q13.1 gain, was observed in 28% of diffuse astrocytoma grade IIs and resulted in partial duplication of the transcription factor MYBL1 with truncation of its C-terminal negative-regulatory domain. A similar recurrent deletion-truncation breakpoint was identified in two angiocentric gliomas in the related gene v-myb avian myeloblastosis viral oncogene homolog (MYB) on 6q23.3. Whole-genome sequencing of a MYBL1-rearranged diffuse astrocytoma grade II demonstrated MYBL1 tandem duplication and few other events. Truncated MYBL1 transcripts identified in this tumor induced anchorage-independent growth in 3T3 cells and tumor formation in nude mice. Truncated transcripts were also expressed in two additional tumors with MYBL1 partial duplication. Our results define clinically relevant molecular subclasses of diffuse PLGGs and highlight a potential role for the MYB family in the biology of low-grade gliomas.
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