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

Lori A. Ramkissoon, Peleg M. Horowitz, Justin M. Craig, Shakti H. Ramkissoon, Benjamin E. Rich, Steven E. Schumacher, Aaron McKenna, Michael S. Lawrence, Guillaume Bergthold, Priscilla K. Brastianos, Barbara Tabak, Matthew D. Ducar, Paul Van Hummelen, Laura E. MacConaill, Tina Pouissant-Young, Yoon-Jae Cho, Hala Taha, Madeha Mahmoud, Daniel C. Bowers, Linda Margraf & 17 others Uri Tabori, Cynthia Hawkins, Roger J. Packer, D. Ashley Hill, Scott L. Pomeroy, Charles G. Eberhart, Ian F. Dunn, Liliana Goumnerova, Gad Getz, Jennifer A. Chan, Sandro Santagata, William C. Hahn, Charles D. Stiles, Azra H. Ligon, Mark W. Kieran, Rameen Beroukhim, Keith L. Ligon

Research output: Contribution to journalArticle

107 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)8188-8193
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number20
DOIs
StatePublished - May 14 2013
Externally publishedYes

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Glioma
Transcription Factors
Pediatrics
Astrocytoma
Neoplasms
Proto-Oncogene Proteins B-raf
myb Genes
3T3 Cells
Growth
Oncogenes
Nude Mice
Paraffin
Formaldehyde
Genome
Mutation

Keywords

  • A-myb
  • ACGH
  • Cancer

ASJC Scopus subject areas

  • General

Cite this

Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. / Ramkissoon, Lori A.; Horowitz, Peleg M.; Craig, Justin M.; Ramkissoon, Shakti H.; Rich, Benjamin E.; Schumacher, Steven E.; McKenna, Aaron; Lawrence, Michael S.; Bergthold, Guillaume; Brastianos, Priscilla K.; Tabak, Barbara; Ducar, Matthew D.; Van Hummelen, Paul; MacConaill, Laura E.; Pouissant-Young, Tina; Cho, Yoon-Jae; Taha, Hala; Mahmoud, Madeha; Bowers, Daniel C.; Margraf, Linda; Tabori, Uri; Hawkins, Cynthia; Packer, Roger J.; Hill, D. Ashley; Pomeroy, Scott L.; Eberhart, Charles G.; Dunn, Ian F.; Goumnerova, Liliana; Getz, Gad; Chan, Jennifer A.; Santagata, Sandro; Hahn, William C.; Stiles, Charles D.; Ligon, Azra H.; Kieran, Mark W.; Beroukhim, Rameen; Ligon, Keith L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 20, 14.05.2013, p. 8188-8193.

Research output: Contribution to journalArticle

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, Y-J, 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 2013, 'Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 20, pp. 8188-8193. https://doi.org/10.1073/pnas.1300252110
Ramkissoon, Lori A. ; Horowitz, Peleg M. ; Craig, Justin M. ; Ramkissoon, Shakti H. ; Rich, Benjamin E. ; Schumacher, Steven E. ; McKenna, Aaron ; Lawrence, Michael S. ; Bergthold, Guillaume ; Brastianos, Priscilla K. ; Tabak, Barbara ; Ducar, Matthew D. ; Van Hummelen, Paul ; MacConaill, Laura E. ; Pouissant-Young, Tina ; Cho, Yoon-Jae ; Taha, Hala ; Mahmoud, Madeha ; Bowers, Daniel C. ; Margraf, Linda ; Tabori, Uri ; Hawkins, Cynthia ; Packer, Roger J. ; Hill, D. Ashley ; Pomeroy, Scott L. ; Eberhart, Charles G. ; Dunn, Ian F. ; Goumnerova, Liliana ; Getz, Gad ; Chan, Jennifer A. ; Santagata, Sandro ; Hahn, William C. ; Stiles, Charles D. ; Ligon, Azra H. ; Kieran, Mark W. ; Beroukhim, Rameen ; Ligon, Keith L. / Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 20. pp. 8188-8193.
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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. 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.",
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author = "Ramkissoon, {Lori A.} and Horowitz, {Peleg M.} and Craig, {Justin M.} and Ramkissoon, {Shakti H.} and Rich, {Benjamin E.} and Schumacher, {Steven E.} and Aaron McKenna and Lawrence, {Michael S.} and Guillaume Bergthold and Brastianos, {Priscilla K.} and Barbara Tabak and Ducar, {Matthew D.} and {Van Hummelen}, Paul and MacConaill, {Laura E.} and Tina Pouissant-Young and Yoon-Jae Cho and Hala Taha and Madeha Mahmoud and Bowers, {Daniel C.} and Linda Margraf and Uri Tabori and Cynthia Hawkins and Packer, {Roger J.} and Hill, {D. Ashley} and Pomeroy, {Scott L.} and Eberhart, {Charles G.} and Dunn, {Ian F.} and Liliana Goumnerova and Gad Getz and Chan, {Jennifer A.} and Sandro Santagata and Hahn, {William C.} and Stiles, {Charles D.} and Ligon, {Azra H.} and Kieran, {Mark W.} and Rameen Beroukhim and Ligon, {Keith L.}",
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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.

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