title: Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1.
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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Lori A
authors: LA
authors: Ramkissoon
authors: Peleg M
authors: PM
authors: Horowitz
authors: Justin M
authors: JM
authors: Craig
authors: Shakti H
authors: SH
authors: Ramkissoon
authors: Benjamin E
authors: BE
authors: Rich
authors: Steven E
authors: SE
authors: Schumacher
authors: Aaron
authors: A
authors: McKenna
authors: Michael S
authors: MS
authors: Lawrence
authors: Guillaume
authors: G
authors: Bergthold
authors: Priscilla K
authors: PK
authors: Brastianos
authors: Barbara
authors: B
authors: Tabak
authors: Matthew D
authors: MD
authors: Ducar
authors: Paul
authors: P
authors: Van Hummelen
authors: Laura E
authors: LE
authors: MacConaill
authors: Tina
authors: T
authors: Pouissant-Young
authors: Yoon-Jae
authors: YJ
authors: Cho
authors: Hala
authors: H
authors: Taha
authors: Madeha
authors: M
authors: Mahmoud
authors: Daniel C
authors: DC
authors: Bowers
authors: Linda
authors: L
authors: Margraf
authors: Uri
authors: U
authors: Tabori
authors: Cynthia
authors: C
authors: Hawkins
authors: Roger J
authors: RJ
authors: Packer
authors: D Ashley
authors: DA
authors: Hill
authors: Scott L
authors: SL
authors: Pomeroy
authors: Charles G
authors: CG
authors: Eberhart
authors: Ian F
authors: IF
authors: Dunn
authors: Liliana
authors: L
authors: Goumnerova
authors: Gad
authors: G
authors: Getz
authors: Jennifer A
authors: JA
authors: Chan
authors: Sandro
authors: S
authors: Santagata
authors: William C
authors: WC
authors: Hahn
authors: Charles D
authors: CD
authors: Stiles
authors: Azra H
authors: AH
authors: Ligon
authors: Mark W
authors: MW
authors: Kieran
authors: Rameen
authors: R
authors: Beroukhim
authors: Keith L
authors: KL
authors: Ligon
mesh_terms: D016475:3T3 Cells; D000483:Alleles; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D005810:Multigene Family; D009154:Mutation; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics*
chemical_list: C088831:MYBL1 protein, human; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators
keywords: A-myb; aCGH; cancer
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