TY - JOUR
T1 - Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1
AU - Ramkissoon, Lori A.
AU - Horowitz, Peleg M.
AU - Craig, Justin M.
AU - Ramkissoon, Shakti H.
AU - Rich, Benjamin E.
AU - Schumacher, Steven E.
AU - McKenna, Aaron
AU - Lawrence, Michael S.
AU - Bergthold, Guillaume
AU - Brastianos, Priscilla K.
AU - Tabak, Barbara
AU - Ducar, Matthew D.
AU - Van Hummelen, Paul
AU - MacConaill, Laura E.
AU - Pouissant-Young, Tina
AU - Cho, Yoon Jae
AU - Taha, Hala
AU - Mahmoud, Madeha
AU - Bowers, Daniel C.
AU - Margraf, Linda
AU - Tabori, Uri
AU - Hawkins, Cynthia
AU - Packer, Roger J.
AU - Hill, D. Ashley
AU - Pomeroy, Scott L.
AU - Eberhart, Charles G.
AU - Dunn, Ian F.
AU - Goumnerova, Liliana
AU - Getz, Gad
AU - Chan, Jennifer A.
AU - Santagata, Sandro
AU - Hahn, William C.
AU - Stiles, Charles D.
AU - Ligon, Azra H.
AU - Kieran, Mark W.
AU - Beroukhim, Rameen
AU - Ligon, Keith L.
PY - 2013/5/14
Y1 - 2013/5/14
N2 - 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.
AB - 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.
KW - A-myb
KW - ACGH
KW - Cancer
UR - http://www.scopus.com/inward/record.url?scp=84877866746&partnerID=8YFLogxK
U2 - 10.1073/pnas.1300252110
DO - 10.1073/pnas.1300252110
M3 - Article
C2 - 23633565
AN - SCOPUS:84877866746
SN - 0027-8424
VL - 110
SP - 8188
EP - 8193
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 20
ER -