The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

Gang Wu; Alexander K. Diaz; Barbara S. Paugh; Sherri L. Rankin; Bensheng Ju; Yongjin Li; Xiaoyan Zhu; Chunxu Qu; Xiang Chen; Junyuan Zhang; John Easton; Michael Edmonson; Xiaotu Ma; Charles Lu; Panduka Nagahawatte; Erin Hedlund; Michael Rusch; Stanley Pounds; Tong Lin; Arzu Onar-Thomas; Robert Huether; Richard Kriwacki; Matthew Parker; Pankaj Gupta; Jared Becksfort; Lei Wei; Heather L. Mulder; Kristy Boggs; Bhavin Vadodaria; Donald Yergeau; Jake C. Russell; Kerri Ochoa; Robert S. Fulton; Lucinda L. Fulton; Chris Jones; Frederick A. Boop; Alberto Broniscer; Cynthia Wetmore; Amar Gajjar; Li Ding; Elaine R. Mardis; Richard K. Wilson; Michael R. Taylor; James R. Downing; David W. Ellison; Jinghui Zhang; Suzanne J. Baker

doi:10.1038/ng.2938

The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

Gang Wu
, Alexander K. Diaz
, Barbara S. Paugh
, Sherri L. Rankin
, Bensheng Ju
, Yongjin Li
, Xiaoyan Zhu
, Chunxu Qu
, Xiang Chen
, Junyuan Zhang
, John Easton
, Michael Edmonson
, Xiaotu Ma
, Charles Lu
, Panduka Nagahawatte
, Erin Hedlund
, Michael Rusch
, Stanley Pounds
, Tong Lin
, Arzu Onar-Thomas

Robert Huether, Richard Kriwacki, Matthew Parker, Pankaj Gupta, Jared Becksfort, Lei Wei, Heather L. Mulder, Kristy Boggs, Bhavin Vadodaria, Donald Yergeau, Jake C. Russell, Kerri Ochoa, Robert S. Fulton, Lucinda L. Fulton, Chris Jones, Frederick A. Boop, Alberto Broniscer, Cynthia Wetmore, Amar Gajjar, Li Ding, Elaine R. Mardis, Richard K. Wilson, Michael R. Taylor, James R. Downing, David W. Ellison, Jinghui Zhang, Suzanne J. Baker

Research output: Contribution to journal › Article › peer-review

874 Scopus citations

Abstract

Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

Original language	English
Pages (from-to)	444-450
Number of pages	7
Journal	Nature Genetics
Volume	46
Issue number	5
DOIs	https://doi.org/10.1038/ng.2938
State	Published - May 2014

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Wu, G., Diaz, A. K., Paugh, B. S., Rankin, S. L., Ju, B., Li, Y., Zhu, X., Qu, C., Chen, X., Zhang, J., Easton, J., Edmonson, M., Ma, X., Lu, C., Nagahawatte, P., Hedlund, E., Rusch, M., Pounds, S., Lin, T., ... Baker, S. J. (2014). The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics, 46(5), 444-450. https://doi.org/10.1038/ng.2938

@article{b22dff784d3d4e079f4e25f906de8bbb,

title = "The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma",

abstract = "Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20\% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32\%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47\% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40\% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68\%, 73\% and 59\% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.",

author = "Gang Wu and Diaz, \{Alexander K.\} and Paugh, \{Barbara S.\} and Rankin, \{Sherri L.\} and Bensheng Ju and Yongjin Li and Xiaoyan Zhu and Chunxu Qu and Xiang Chen and Junyuan Zhang and John Easton and Michael Edmonson and Xiaotu Ma and Charles Lu and Panduka Nagahawatte and Erin Hedlund and Michael Rusch and Stanley Pounds and Tong Lin and Arzu Onar-Thomas and Robert Huether and Richard Kriwacki and Matthew Parker and Pankaj Gupta and Jared Becksfort and Lei Wei and Mulder, \{Heather L.\} and Kristy Boggs and Bhavin Vadodaria and Donald Yergeau and Russell, \{Jake C.\} and Kerri Ochoa and Fulton, \{Robert S.\} and Fulton, \{Lucinda L.\} and Chris Jones and Boop, \{Frederick A.\} and Alberto Broniscer and Cynthia Wetmore and Amar Gajjar and Li Ding and Mardis, \{Elaine R.\} and Wilson, \{Richard K.\} and Taylor, \{Michael R.\} and Downing, \{James R.\} and Ellison, \{David W.\} and Jinghui Zhang and Baker, \{Suzanne J.\}",

note = "Funding Information: We thank the St. Jude Children{\textquoteright}s Research Hospital Tissue Resource Facility and B. Gordon, M. Johnson, S. Brown and C. Calabrese in the St. Jude Small Animal Imaging Core for expert assistance with intracranial implantations. We thank E. Shore and A. Culbert (University of Pennsylvania) for helpful advice with antibody selection. This work was supported by the St. Jude Children{\textquoteright}s Research Hospital–Washington University Pediatric Cancer Genome Project, by the American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children{\textquoteright}s Research Hospital, by grants from the US National Institutes of Health (P01 CA096832 to S.J.B., Jinghui Zhang and D.W.E. and R01 CA135554 to S.J.B.), by the Cure Starts Now Foundation and the Smile for Sophie Forever Foundation, and by Tyler{\textquoteright}s Treehouse and Musicians Against Childhood Cancer.",

year = "2014",

month = may,

doi = "10.1038/ng.2938",

language = "English",

volume = "46",

pages = "444--450",

journal = "Nature Genetics",

issn = "1061-4036",

number = "5",

}

Wu, G, Diaz, AK, Paugh, BS, Rankin, SL, Ju, B, Li, Y, Zhu, X, Qu, C, Chen, X, Zhang, J, Easton, J, Edmonson, M, Ma, X, Lu, C, Nagahawatte, P, Hedlund, E, Rusch, M, Pounds, S, Lin, T, Onar-Thomas, A, Huether, R, Kriwacki, R, Parker, M, Gupta, P, Becksfort, J, Wei, L, Mulder, HL, Boggs, K, Vadodaria, B, Yergeau, D, Russell, JC, Ochoa, K, Fulton, RS , Fulton, LL, Jones, C, Boop, FA, Broniscer, A, Wetmore, C, Gajjar, A, Ding, L, Mardis, ER, Wilson, RK, Taylor, MR, Downing, JR, Ellison, DW, Zhang, J & Baker, SJ 2014, 'The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma', Nature Genetics, vol. 46, no. 5, pp. 444-450. https://doi.org/10.1038/ng.2938

TY - JOUR

T1 - The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

AU - Wu, Gang

AU - Diaz, Alexander K.

AU - Paugh, Barbara S.

AU - Rankin, Sherri L.

AU - Ju, Bensheng

AU - Li, Yongjin

AU - Zhu, Xiaoyan

AU - Qu, Chunxu

AU - Chen, Xiang

AU - Zhang, Junyuan

AU - Easton, John

AU - Edmonson, Michael

AU - Ma, Xiaotu

AU - Lu, Charles

AU - Nagahawatte, Panduka

AU - Hedlund, Erin

AU - Rusch, Michael

AU - Pounds, Stanley

AU - Lin, Tong

AU - Onar-Thomas, Arzu

AU - Huether, Robert

AU - Kriwacki, Richard

AU - Parker, Matthew

AU - Gupta, Pankaj

AU - Becksfort, Jared

AU - Wei, Lei

AU - Mulder, Heather L.

AU - Boggs, Kristy

AU - Vadodaria, Bhavin

AU - Yergeau, Donald

AU - Russell, Jake C.

AU - Ochoa, Kerri

AU - Fulton, Robert S.

AU - Fulton, Lucinda L.

AU - Jones, Chris

AU - Boop, Frederick A.

AU - Broniscer, Alberto

AU - Wetmore, Cynthia

AU - Gajjar, Amar

AU - Ding, Li

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Taylor, Michael R.

AU - Downing, James R.

AU - Ellison, David W.

AU - Zhang, Jinghui

AU - Baker, Suzanne J.

N1 - Funding Information: We thank the St. Jude Children’s Research Hospital Tissue Resource Facility and B. Gordon, M. Johnson, S. Brown and C. Calabrese in the St. Jude Small Animal Imaging Core for expert assistance with intracranial implantations. We thank E. Shore and A. Culbert (University of Pennsylvania) for helpful advice with antibody selection. This work was supported by the St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project, by the American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children’s Research Hospital, by grants from the US National Institutes of Health (P01 CA096832 to S.J.B., Jinghui Zhang and D.W.E. and R01 CA135554 to S.J.B.), by the Cure Starts Now Foundation and the Smile for Sophie Forever Foundation, and by Tyler’s Treehouse and Musicians Against Childhood Cancer.

PY - 2014/5

Y1 - 2014/5

N2 - Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

AB - Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

UR - https://www.scopus.com/pages/publications/84899526966

U2 - 10.1038/ng.2938

DO - 10.1038/ng.2938

M3 - Article

C2 - 24705251

AN - SCOPUS:84899526966

SN - 1061-4036

VL - 46

SP - 444

EP - 450

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma

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