Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

Pawel Buczkowicz; Christine Hoeman; Patricia Rakopoulos; Sanja Pajovic; Louis Letourneau; Misko Dzamba; Andrew Morrison; Peter Lewis; Eric Bouffet; Ute Bartels; Jennifer Zuccaro; Sameer Agnihotri; Scott Ryall; Mark Barszczyk; Yevgen Chornenkyy; Mathieu Bourgey; Guillaume Bourque; Alexandre Montpetit; Francisco Cordero; Pedro Castelo-Branco; Joshua Mangerel; Uri Tabori; King Ching Ho; Annie Huang; Kathryn R. Taylor; Alan Mackay; Anne E. Bendel; Javad Nazarian; Jason R. Fangusaro; Matthias A. Karajannis; David Zagzag; Nicholas K. Foreman; Andrew Donson; Julia V. Hegert; Amy Smith; Jennifer Chan; Lucy Lafay-Cousin; Sandra Dunn; Juliette Hukin; Chris Dunham; Katrin Scheinemann; Jean Michaud; Shayna Zelcer; David Ramsay; Jason Cain; Cameron Brennan; Mark M. Souweidane; Chris Jones; C. David Allis; Michael Brudno; Oren Becher; Cynthia Hawkins

doi:10.1038/ng.2936

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

Pawel Buczkowicz, Christine Hoeman, Patricia Rakopoulos, Sanja Pajovic, Louis Letourneau, Misko Dzamba, Andrew Morrison, Peter Lewis, Eric Bouffet, Ute Bartels, Jennifer Zuccaro, Sameer Agnihotri, Scott Ryall, Mark Barszczyk, Yevgen Chornenkyy, Mathieu Bourgey, Guillaume Bourque, Alexandre Montpetit, Francisco Cordero, Pedro Castelo-BrancoJoshua Mangerel, Uri Tabori, King Ching Ho, Annie Huang, Kathryn R. Taylor, Alan Mackay, Anne E. Bendel, Javad Nazarian, Jason R. Fangusaro, Matthias A. Karajannis, David Zagzag, Nicholas K. Foreman, Andrew Donson, Julia V. Hegert, Amy Smith, Jennifer Chan, Lucy Lafay-Cousin, Sandra Dunn, Juliette Hukin, Chris Dunham, Katrin Scheinemann, Jean Michaud, Shayna Zelcer, David Ramsay, Jason Cain, Cameron Brennan, Mark M. Souweidane, Chris Jones, C. David Allis, Michael Brudno, Oren Becher, Cynthia Hawkins^*

^*Corresponding author for this work

Pediatrics

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

497 Scopus citations

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Original language	English (US)
Pages (from-to)	451-456
Number of pages	6
Journal	Nature Genetics
Volume	46
Issue number	5
DOIs	https://doi.org/10.1038/ng.2936
State	Published - May 2014

Funding

We would like to thank all of the patients and families for donating tissue for this research. This work was supported by the Canadian Institutes of Health Research (CIHR, MOP 115004) and was funded in part by a Genome Canada/CIHR grant (cofunding from Genome BC, Génome Québec, CIHR-ICR (Institute for Cancer Research) and C17, through the Genome Canada/CIHR joint ATID Competition (project title: The Canadian Paediatric Cancer Genome Consortium (CPCGC): Translating Next-Generation Sequencing Technologies into Improved Therapies for High-Risk Childhood Cancer)). P.B. is a recipient of a CIHR Doctoral Frederick Banting and Charles Best Canada Graduate Scholarships award. O.B. is a Damon Runyon Clinical Investigator and is supported by the US Department of Defense and the Pediatric Brain Tumor Foundation. C.J., A. Mackay and K.R.T. acknowledge National Health Service (NHS) funding to the Biomedical Research Centre and support from the Stavros Niarchos Foundation. Sample collection for M.A.K. and D.Z. was supported in part by grant UL1TR000038 from the National Center for Research Resources, US National Institutes of Health and by grant 5P30CA016087-32 from the National Cancer Institute.

ASJC Scopus subject areas

Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2936

Cite this

Buczkowicz, P., Hoeman, C., Rakopoulos, P., Pajovic, S., Letourneau, L., Dzamba, M., Morrison, A., Lewis, P., Bouffet, E., Bartels, U., Zuccaro, J., Agnihotri, S., Ryall, S., Barszczyk, M., Chornenkyy, Y., Bourgey, M., Bourque, G., Montpetit, A., Cordero, F., ... Hawkins, C. (2014). Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nature Genetics, 46(5), 451-456. https://doi.org/10.1038/ng.2936

@article{710814145eae4834a20b7e3d53beaad9,

title = "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations",

abstract = "Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.",

author = "Pawel Buczkowicz and Christine Hoeman and Patricia Rakopoulos and Sanja Pajovic and Louis Letourneau and Misko Dzamba and Andrew Morrison and Peter Lewis and Eric Bouffet and Ute Bartels and Jennifer Zuccaro and Sameer Agnihotri and Scott Ryall and Mark Barszczyk and Yevgen Chornenkyy and Mathieu Bourgey and Guillaume Bourque and Alexandre Montpetit and Francisco Cordero and Pedro Castelo-Branco and Joshua Mangerel and Uri Tabori and Ho, {King Ching} and Annie Huang and Taylor, {Kathryn R.} and Alan Mackay and Bendel, {Anne E.} and Javad Nazarian and Fangusaro, {Jason R.} and Karajannis, {Matthias A.} and David Zagzag and Foreman, {Nicholas K.} and Andrew Donson and Hegert, {Julia V.} and Amy Smith and Jennifer Chan and Lucy Lafay-Cousin and Sandra Dunn and Juliette Hukin and Chris Dunham and Katrin Scheinemann and Jean Michaud and Shayna Zelcer and David Ramsay and Jason Cain and Cameron Brennan and Souweidane, {Mark M.} and Chris Jones and Allis, {C. David} and Michael Brudno and Oren Becher and Cynthia Hawkins",

note = "Funding Information: We would like to thank all of the patients and families for donating tissue for this research. This work was supported by the Canadian Institutes of Health Research (CIHR, MOP 115004) and was funded in part by a Genome Canada/CIHR grant (cofunding from Genome BC, G{\'e}nome Qu{\'e}bec, CIHR-ICR (Institute for Cancer Research) and C17, through the Genome Canada/CIHR joint ATID Competition (project title: The Canadian Paediatric Cancer Genome Consortium (CPCGC): Translating Next-Generation Sequencing Technologies into Improved Therapies for High-Risk Childhood Cancer)). P.B. is a recipient of a CIHR Doctoral Frederick Banting and Charles Best Canada Graduate Scholarships award. O.B. is a Damon Runyon Clinical Investigator and is supported by the US Department of Defense and the Pediatric Brain Tumor Foundation. C.J., A. Mackay and K.R.T. acknowledge National Health Service (NHS) funding to the Biomedical Research Centre and support from the Stavros Niarchos Foundation. Sample collection for M.A.K. and D.Z. was supported in part by grant UL1TR000038 from the National Center for Research Resources, US National Institutes of Health and by grant 5P30CA016087-32 from the National Cancer Institute.",

year = "2014",

month = may,

doi = "10.1038/ng.2936",

language = "English (US)",

volume = "46",

pages = "451--456",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "5",

}

Buczkowicz, P, Hoeman, C, Rakopoulos, P, Pajovic, S, Letourneau, L, Dzamba, M, Morrison, A, Lewis, P, Bouffet, E, Bartels, U, Zuccaro, J, Agnihotri, S, Ryall, S, Barszczyk, M, Chornenkyy, Y, Bourgey, M, Bourque, G, Montpetit, A, Cordero, F, Castelo-Branco, P, Mangerel, J, Tabori, U, Ho, KC, Huang, A, Taylor, KR, Mackay, A, Bendel, AE, Nazarian, J, Fangusaro, JR, Karajannis, MA, Zagzag, D, Foreman, NK, Donson, A, Hegert, JV, Smith, A, Chan, J, Lafay-Cousin, L, Dunn, S, Hukin, J, Dunham, C, Scheinemann, K, Michaud, J, Zelcer, S, Ramsay, D, Cain, J, Brennan, C, Souweidane, MM, Jones, C, Allis, CD, Brudno, M, Becher, O & Hawkins, C 2014, 'Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations', Nature Genetics, vol. 46, no. 5, pp. 451-456. https://doi.org/10.1038/ng.2936

TY - JOUR

T1 - Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

AU - Buczkowicz, Pawel

AU - Hoeman, Christine

AU - Rakopoulos, Patricia

AU - Pajovic, Sanja

AU - Letourneau, Louis

AU - Dzamba, Misko

AU - Morrison, Andrew

AU - Lewis, Peter

AU - Bouffet, Eric

AU - Bartels, Ute

AU - Zuccaro, Jennifer

AU - Agnihotri, Sameer

AU - Ryall, Scott

AU - Barszczyk, Mark

AU - Chornenkyy, Yevgen

AU - Bourgey, Mathieu

AU - Bourque, Guillaume

AU - Montpetit, Alexandre

AU - Cordero, Francisco

AU - Castelo-Branco, Pedro

AU - Mangerel, Joshua

AU - Tabori, Uri

AU - Ho, King Ching

AU - Huang, Annie

AU - Taylor, Kathryn R.

AU - Mackay, Alan

AU - Bendel, Anne E.

AU - Nazarian, Javad

AU - Fangusaro, Jason R.

AU - Karajannis, Matthias A.

AU - Zagzag, David

AU - Foreman, Nicholas K.

AU - Donson, Andrew

AU - Hegert, Julia V.

AU - Smith, Amy

AU - Chan, Jennifer

AU - Lafay-Cousin, Lucy

AU - Dunn, Sandra

AU - Hukin, Juliette

AU - Dunham, Chris

AU - Scheinemann, Katrin

AU - Michaud, Jean

AU - Zelcer, Shayna

AU - Ramsay, David

AU - Cain, Jason

AU - Brennan, Cameron

AU - Souweidane, Mark M.

AU - Jones, Chris

AU - Allis, C. David

AU - Brudno, Michael

AU - Becher, Oren

AU - Hawkins, Cynthia

N1 - Funding Information: We would like to thank all of the patients and families for donating tissue for this research. This work was supported by the Canadian Institutes of Health Research (CIHR, MOP 115004) and was funded in part by a Genome Canada/CIHR grant (cofunding from Genome BC, Génome Québec, CIHR-ICR (Institute for Cancer Research) and C17, through the Genome Canada/CIHR joint ATID Competition (project title: The Canadian Paediatric Cancer Genome Consortium (CPCGC): Translating Next-Generation Sequencing Technologies into Improved Therapies for High-Risk Childhood Cancer)). P.B. is a recipient of a CIHR Doctoral Frederick Banting and Charles Best Canada Graduate Scholarships award. O.B. is a Damon Runyon Clinical Investigator and is supported by the US Department of Defense and the Pediatric Brain Tumor Foundation. C.J., A. Mackay and K.R.T. acknowledge National Health Service (NHS) funding to the Biomedical Research Centre and support from the Stavros Niarchos Foundation. Sample collection for M.A.K. and D.Z. was supported in part by grant UL1TR000038 from the National Center for Research Resources, US National Institutes of Health and by grant 5P30CA016087-32 from the National Cancer Institute.

PY - 2014/5

Y1 - 2014/5

N2 - Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

AB - Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

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U2 - 10.1038/ng.2936

DO - 10.1038/ng.2936

M3 - Article

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AN - SCOPUS:84899570180

SN - 1061-4036

VL - 46

SP - 451

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JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

Abstract

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UN SDGs

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