Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1

Lori A. Ramkissoon, Peleg M. Horowitz, Justin M. Craig, Shakti H. Ramkissoon, Benjamin E. Rich, Steven E. Schumacher, Aaron McKenna, Michael S. Lawrence, Guillaume Bergthold, Priscilla K. Brastianos, Barbara Tabak, Matthew D. Ducar, Paul Van Hummelen, Laura E. MacConaill, Tina Pouissant-Young, Yoon Jae Cho, Hala Taha, Madeha Mahmoud, Daniel C. Bowers, Linda MargrafUri Tabori, Cynthia Hawkins, Roger J. Packer, D. Ashley Hill, Scott L. Pomeroy, Charles G. Eberhart, Ian F. Dunn, Liliana Goumnerova, Gad Getz, Jennifer A. Chan, Sandro Santagata, William C. Hahn, Charles D. Stiles, Azra H. Ligon, Mark W. Kieran, Rameen Beroukhim, Keith L. Ligon

Research output: Contribution to journalArticle

116 Scopus citations

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. Asimilar 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.

Original languageEnglish (US)
Pages (from-to)8188-8193
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number20
DOIs
StatePublished - May 14 2013

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Keywords

  • A-myb
  • ACGH
  • Cancer

ASJC Scopus subject areas

  • General

Cite this

Ramkissoon, L. A., Horowitz, P. M., Craig, J. M., Ramkissoon, S. H., Rich, B. E., Schumacher, S. E., McKenna, A., Lawrence, M. S., Bergthold, G., Brastianos, P. K., Tabak, B., Ducar, M. D., Van Hummelen, P., MacConaill, L. E., Pouissant-Young, T., Cho, Y. J., Taha, H., Mahmoud, M., Bowers, D. C., ... Ligon, K. L. (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 of the United States of America, 110(20), 8188-8193. https://doi.org/10.1073/pnas.1300252110