Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factorMYBL1

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.cancer | aCGH | A-myb

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

“…S5A), presumably leading to the expression of a specific constitutively active truncated protein, as described previously (23,28). Similar human BRAF gene truncations or fusions have been reported in human brain, pancreatic, and prostate tumors (28)(29)(30)(31)(32)(33)(34). In some cases, the insertional landscape exhibited genetic specificities consistent with respective tumor indications (Fig.…”

Histopathological Features of Common Pediatric Brain Tumors

“…In a similar analysis of grade II gliomas, 28 % were shown to have partial duplication of the transcription factor MYBL1 [ 10 ]. Given the availability of specifi c therapeutic inhibitors of such pathways, histopathological diagnosis with supplemental molecular analysis of tumors may one day offer more patient-specifi c treatments and prognostication for these tumors.…”

MicroRNA-548c-3p inhibits T98G glioma cell proliferation and migration by downregulating c-Myb

“…In various types of human cancer, mutations have been identified in the Myb gene: Overexpression of c-Myb contributes to transformation in pediatric T-cell acute lymphocyte leukemia, pancreatic tumors and colon tumors (18,19). Rearrangements and amplifications of Myb have been identified in ~25% of diffuse cerebral gliomas (20). These results suggest that c-Myb is involved in glioma tumorigenesis.…”