Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Adam M. Fontebasso, Simon Papillon-Cavanagh, Jeremy Schwartzentruber, Hamid Nikbakht, Noha Gerges, Pierre Olivier Fiset, Denise Bechet, Damien Faury, Nicolas De Jay, Lori A. Ramkissoon, Aoife Corcoran, David T W Jones, Dominik Sturm, Pascal Johann, Tadanori Tomita, Stewart Goldman, Mahmoud Nagib, Anne Bendel, Liliana Goumnerova, Daniel C. Bowers & 28 others Jeffrey R. Leonard, Joshua B. Rubin, Tord Alden, Samuel Browd, J. Russell Geyer, Sarah Leary, George Jallo, Kenneth Cohen, Nalin Gupta, Michael D. Prados, Anne Sophie Carret, Benjamin Ellezam, Louis Crevier, A. Klekner, L. Bognár, P. Hauser, M. Garami, John Myseros, Zhifeng Dong, Peter M. Siegel, Hayley Malkin, Azra H. Ligon, Steffen Albrecht, Stefan M. Pfister, Keith L. Ligon, Jacek Majewski, Nada Jabado, Mark W. Kieran

Research output: Contribution to journalArticle

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Abstract

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

Original languageEnglish
Pages (from-to)462-466
Number of pages5
JournalNature Genetics
Volume46
Issue number5
DOIs
Publication statusPublished - 2014

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Astrocytoma
Pediatrics
Histones
Mutation
Neoplasms
Bone Morphogenetic Proteins
Exome
Pons
DNA Methylation
Epigenomics
Up-Regulation
Phenotype
Biopsy
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Fontebasso, A. M., Papillon-Cavanagh, S., Schwartzentruber, J., Nikbakht, H., Gerges, N., Fiset, P. O., ... Kieran, M. W. (2014). Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nature Genetics, 46(5), 462-466. https://doi.org/10.1038/ng.2950

Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. / Fontebasso, Adam M.; Papillon-Cavanagh, Simon; Schwartzentruber, Jeremy; Nikbakht, Hamid; Gerges, Noha; Fiset, Pierre Olivier; Bechet, Denise; Faury, Damien; De Jay, Nicolas; Ramkissoon, Lori A.; Corcoran, Aoife; Jones, David T W; Sturm, Dominik; Johann, Pascal; Tomita, Tadanori; Goldman, Stewart; Nagib, Mahmoud; Bendel, Anne; Goumnerova, Liliana; Bowers, Daniel C.; Leonard, Jeffrey R.; Rubin, Joshua B.; Alden, Tord; Browd, Samuel; Geyer, J. Russell; Leary, Sarah; Jallo, George; Cohen, Kenneth; Gupta, Nalin; Prados, Michael D.; Carret, Anne Sophie; Ellezam, Benjamin; Crevier, Louis; Klekner, A.; Bognár, L.; Hauser, P.; Garami, M.; Myseros, John; Dong, Zhifeng; Siegel, Peter M.; Malkin, Hayley; Ligon, Azra H.; Albrecht, Steffen; Pfister, Stefan M.; Ligon, Keith L.; Majewski, Jacek; Jabado, Nada; Kieran, Mark W.

In: Nature Genetics, Vol. 46, No. 5, 2014, p. 462-466.

Research output: Contribution to journalArticle

Fontebasso, AM, Papillon-Cavanagh, S, Schwartzentruber, J, Nikbakht, H, Gerges, N, Fiset, PO, Bechet, D, Faury, D, De Jay, N, Ramkissoon, LA, Corcoran, A, Jones, DTW, Sturm, D, Johann, P, Tomita, T, Goldman, S, Nagib, M, Bendel, A, Goumnerova, L, Bowers, DC, Leonard, JR, Rubin, JB, Alden, T, Browd, S, Geyer, JR, Leary, S, Jallo, G, Cohen, K, Gupta, N, Prados, MD, Carret, AS, Ellezam, B, Crevier, L, Klekner, A, Bognár, L, Hauser, P, Garami, M, Myseros, J, Dong, Z, Siegel, PM, Malkin, H, Ligon, AH, Albrecht, S, Pfister, SM, Ligon, KL, Majewski, J, Jabado, N & Kieran, MW 2014, 'Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma', Nature Genetics, vol. 46, no. 5, pp. 462-466. https://doi.org/10.1038/ng.2950
Fontebasso AM, Papillon-Cavanagh S, Schwartzentruber J, Nikbakht H, Gerges N, Fiset PO et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nature Genetics. 2014;46(5):462-466. https://doi.org/10.1038/ng.2950
Fontebasso, Adam M. ; Papillon-Cavanagh, Simon ; Schwartzentruber, Jeremy ; Nikbakht, Hamid ; Gerges, Noha ; Fiset, Pierre Olivier ; Bechet, Denise ; Faury, Damien ; De Jay, Nicolas ; Ramkissoon, Lori A. ; Corcoran, Aoife ; Jones, David T W ; Sturm, Dominik ; Johann, Pascal ; Tomita, Tadanori ; Goldman, Stewart ; Nagib, Mahmoud ; Bendel, Anne ; Goumnerova, Liliana ; Bowers, Daniel C. ; Leonard, Jeffrey R. ; Rubin, Joshua B. ; Alden, Tord ; Browd, Samuel ; Geyer, J. Russell ; Leary, Sarah ; Jallo, George ; Cohen, Kenneth ; Gupta, Nalin ; Prados, Michael D. ; Carret, Anne Sophie ; Ellezam, Benjamin ; Crevier, Louis ; Klekner, A. ; Bognár, L. ; Hauser, P. ; Garami, M. ; Myseros, John ; Dong, Zhifeng ; Siegel, Peter M. ; Malkin, Hayley ; Ligon, Azra H. ; Albrecht, Steffen ; Pfister, Stefan M. ; Ligon, Keith L. ; Majewski, Jacek ; Jabado, Nada ; Kieran, Mark W. / Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. In: Nature Genetics. 2014 ; Vol. 46, No. 5. pp. 462-466.
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