Scientific Publications

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

Publication TypeJournal Article
AuthorsRamkissoon, LA, Horowitz PM, Craig JM, Ramkissoon SH, Rich BE, Schumacher SE, McKenna A., Lawrence MS, Bergthold G., Brastianos PK, Tabak B., Ducar MD, Van Hummelen P., Macconaill LE, Pouissant-Young T., Cho YJ, Taha H., Mahmoud M., Bowers DC, Margraf L., Tabori U., Hawkins C., Packer RJ, Hill DA, Pomeroy SL, Eberhart CG, Dunn IF, Goumnerova L., Getz G., Chan JA, Santagata S., Hahn WC, Stiles CD, Ligon AH, Kieran MW, Beroukhim R., and Ligon KL
AbstractPediatric 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.
Year of Publication2013
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue20
Pages8188-93
Date Published (YYYY/MM/DD)2013/05/14
ISSN Number0027-8424
DOI10.1073/pnas.1300252110
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/23633565?dopt=Abstract