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.
Source: Genomic analysis of diffuse
pediatric low-grade gliomas identifies recurrent oncogenic truncating
rearrangements in the transcription factor MYBL1. Ramkissoon 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, Ligon KL. Proc Natl Acad Sci U S A. 2013 Apr 30.
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