Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma

Kathryn R. Taylor; Alan Mackay; Nathalène Truffaux; Yaron S. Butterfield; Olena Morozova; Cathy Philippe; David Castel; Catherine S. Grasso; Maria Vinci; Diana Carvalho; Angel M. Carcaboso; Carmen De Torres; Ofelia Cruz; Jaume Mora; Natacha Entz-Werle; Wendy J. Ingram; Michelle Monje; Darren Hargrave; Alex N. Bullock; Stéphanie Puget; Stephen Yip; Chris Jones; Jacques Grill

doi:10.1038/ng.2925

Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma

Kathryn R. Taylor, Alan Mackay, Nathalène Truffaux, Yaron S. Butterfield, Olena Morozova, Cathy Philippe, David Castel, Catherine S. Grasso, Maria Vinci, Diana Carvalho, Angel M. Carcaboso, Carmen De Torres, Ofelia Cruz, Jaume Mora, Natacha Entz-Werle, Wendy J. Ingram, Michelle Monje, Darren Hargrave, Alex N. Bullock, Stéphanie PugetStephen Yip, Chris Jones, Jacques Grill

Résultats de recherche: Contribution à un journal › Article › Revue par des pairs

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Résumé

Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-Î 2 signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.

langue originale	Anglais
Pages (de - à)	457-461
Nombre de pages	5
journal	Nature Genetics
Volume	46
Numéro de publication	5
Les DOIs	https://doi.org/10.1038/ng.2925
état	Publié - 1 janv. 2014
Modification externe	Oui

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10.1038/ng.2925

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Taylor, K. R., Mackay, A., Truffaux, N., Butterfield, Y. S., Morozova, O., Philippe, C., Castel, D., Grasso, C. S., Vinci, M., Carvalho, D., Carcaboso, A. M., De Torres, C., Cruz, O., Mora, J., Entz-Werle, N., Ingram, W. J., Monje, M., Hargrave, D., Bullock, A. N., ... Grill, J. (2014). Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nature Genetics, 46(5), 457-461. https://doi.org/10.1038/ng.2925

@article{dd1cc77163bd410e940f6e44e4caf788,

title = "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma",

abstract = "Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-{\^I} 2 signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.",

author = "Taylor, {Kathryn R.} and Alan Mackay and Nathal{\`e}ne Truffaux and Butterfield, {Yaron S.} and Olena Morozova and Cathy Philippe and David Castel and Grasso, {Catherine S.} and Maria Vinci and Diana Carvalho and Carcaboso, {Angel M.} and {De Torres}, Carmen and Ofelia Cruz and Jaume Mora and Natacha Entz-Werle and Ingram, {Wendy J.} and Michelle Monje and Darren Hargrave and Bullock, {Alex N.} and St{\'e}phanie Puget and Stephen Yip and Chris Jones and Jacques Grill",

note = "Funding Information: This study was funded by the Cancer Research UK Genomics Initiative (A14078) and makes use of data generated by the St. Jude Children{\textquoteright}s Research Hospital–Washington University Pediatric Cancer Genome Project. We are grateful to the DIPG Preclinical Consortium funded by The Cure Starts Now and the Lyla Nsouli Foundation for RNA-seq data. This work is supported by the Stavros Niarchos Foundation, Abbie{\textquoteright}s Army, the Lyla Nsouli Foundation, the Royal Marsden Hospital Children{\textquoteright}s Department Fund and Fondo Alicia Pueyo. M.M. gratefully acknowledges funding by the National Institutes of Neurological Disease and Stroke (NINDS; grant K08NS070926), Alex{\textquoteright}s Lemonade Stand Foundation, the McKenna Claire Foundation and the Dylan Jewett, Elizabeth Stein, Connor Johnson and Zoey Ganesh Memorial Funds. C.P. acknowledges funding from the Agence National de la Recherche. N.T., C.P. and J.G. acknowledge funding from the charity l{\textquoteright}Etoile de Martin, and N.E.-W. acknowledges support from Enfants et Sant{\'e}. A.M.C. acknowledges funding from the Fundaci{\'o}n Cient{\'i}fica de la Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer. W.J.I. acknowledges funding from the Children{\textquoteright}s Health Foundation Queensland and the Brainchild Foundation. The Structural Genomics Consortium is a registered charity (1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada",

year = "2014",

month = jan,

day = "1",

doi = "10.1038/ng.2925",

language = "English",

volume = "46",

pages = "457--461",

journal = "Nature Genetics",

issn = "1061-4036",

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Taylor, KR, Mackay, A, Truffaux, N, Butterfield, YS, Morozova, O, Philippe, C, Castel, D, Grasso, CS, Vinci, M, Carvalho, D, Carcaboso, AM, De Torres, C, Cruz, O, Mora, J, Entz-Werle, N, Ingram, WJ, Monje, M, Hargrave, D, Bullock, AN, Puget, S, Yip, S, Jones, C & Grill, J 2014, 'Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma', Nature Genetics, VOL. 46, Numéro 5, p. 457-461. https://doi.org/10.1038/ng.2925

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T1 - Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma

AU - Taylor, Kathryn R.

AU - Mackay, Alan

AU - Truffaux, Nathalène

AU - Butterfield, Yaron S.

AU - Morozova, Olena

AU - Philippe, Cathy

AU - Castel, David

AU - Grasso, Catherine S.

AU - Vinci, Maria

AU - Carvalho, Diana

AU - Carcaboso, Angel M.

AU - De Torres, Carmen

AU - Cruz, Ofelia

AU - Mora, Jaume

AU - Entz-Werle, Natacha

AU - Ingram, Wendy J.

AU - Monje, Michelle

AU - Hargrave, Darren

AU - Bullock, Alex N.

AU - Puget, Stéphanie

AU - Yip, Stephen

AU - Jones, Chris

AU - Grill, Jacques

N1 - Funding Information: This study was funded by the Cancer Research UK Genomics Initiative (A14078) and makes use of data generated by the St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project. We are grateful to the DIPG Preclinical Consortium funded by The Cure Starts Now and the Lyla Nsouli Foundation for RNA-seq data. This work is supported by the Stavros Niarchos Foundation, Abbie’s Army, the Lyla Nsouli Foundation, the Royal Marsden Hospital Children’s Department Fund and Fondo Alicia Pueyo. M.M. gratefully acknowledges funding by the National Institutes of Neurological Disease and Stroke (NINDS; grant K08NS070926), Alex’s Lemonade Stand Foundation, the McKenna Claire Foundation and the Dylan Jewett, Elizabeth Stein, Connor Johnson and Zoey Ganesh Memorial Funds. C.P. acknowledges funding from the Agence National de la Recherche. N.T., C.P. and J.G. acknowledge funding from the charity l’Etoile de Martin, and N.E.-W. acknowledges support from Enfants et Santé. A.M.C. acknowledges funding from the Fundación Científica de la Asociación Española Contra el Cáncer. W.J.I. acknowledges funding from the Children’s Health Foundation Queensland and the Brainchild Foundation. The Structural Genomics Consortium is a registered charity (1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9-12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) and have been shown to constitutively activate the BMP-TGF-Î 2 signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.

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