Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Liwei Zhang; Lee H. Chen; Hong Wan; Rui Yang; Zhaohui Wang; Jie Feng; Shaohua Yang; Siân Jones; Sizhen Wang; Weixin Zhou; Huishan Zhu; Patrick J. Killela; Junting Zhang; Zhen Wu; Guilin Li; Shuyu Hao; Yu Wang; Joseph B. Webb; Henry S. Friedman; Allan H. Friedman; Roger E. McLendon; Yiping He; Zachary J. Reitman; Darell D. Bigner; Hai Yan

doi:10.1038/ng.2995

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Liwei Zhang, Lee H. Chen, Hong Wan, Rui Yang, Zhaohui Wang, Jie Feng, Shaohua Yang, Siân Jones, Sizhen Wang, Weixin Zhou, Huishan Zhu, Patrick J. Killela, Junting Zhang, Zhen Wu, Guilin Li, Shuyu Hao, Yu Wang, Joseph B. Webb, Henry S. Friedman, Allan H. FriedmanRoger E. McLendon, Yiping He, Zachary J. Reitman, Darell D. Bigner, Hai Yan

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Abstract

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Original language	English
Pages (from-to)	726-730
Number of pages	5
Journal	Nature Genetics
Volume	46
Issue number	7
DOIs	https://doi.org/10.1038/ng.2995
State	Published - Jul 2014

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Zhang, L., Chen, L. H., Wan, H., Yang, R., Wang, Z., Feng, J., Yang, S., Jones, S., Wang, S., Zhou, W., Zhu, H., Killela, P. J., Zhang, J., Wu, Z., Li, G., Hao, S., Wang, Y., Webb, J. B., Friedman, H. S., ... Yan, H. (2014). Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nature Genetics, 46(7), 726-730. https://doi.org/10.1038/ng.2995

@article{10bc43a2ee86493a8f36f6db4cbe74a4,

title = "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas",

abstract = "Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.",

author = "Liwei Zhang and Chen, {Lee H.} and Hong Wan and Rui Yang and Zhaohui Wang and Jie Feng and Shaohua Yang and Si{\^a}n Jones and Sizhen Wang and Weixin Zhou and Huishan Zhu and Killela, {Patrick J.} and Junting Zhang and Zhen Wu and Guilin Li and Shuyu Hao and Yu Wang and Webb, {Joseph B.} and Friedman, {Henry S.} and Friedman, {Allan H.} and McLendon, {Roger E.} and Yiping He and Reitman, {Zachary J.} and Bigner, {Darell D.} and Hai Yan",

note = "Funding Information: This study was partly supported by National Cancer Institute grant R01CA140316 (H.Y.), the American Cancer Society (RSG-10-126-01-CCE) (H.Y.), a Pediatric Brain Tumor Foundation Institute grant (D.D.B.), a Voices Against Brain Cancer Foundation grant (D.D.B.), a James S. McDonnell Foundation grant (H.Y.), The V Foundation (H.Y.), an Accelerate Brain Cancer Cure Foundation grant (H.Y.), a Pediatric Brain Tumor Foundation Institute at Duke Early Career Award (Z.J.R.) and Natural Science Foundation of China grants 30772237 and 81241078 (L.Z.).",

year = "2014",

month = jul,

doi = "10.1038/ng.2995",

language = "English",

volume = "46",

pages = "726--730",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

}

Zhang, L, Chen, LH, Wan, H, Yang, R, Wang, Z, Feng, J, Yang, S, Jones, S, Wang, S, Zhou, W, Zhu, H, Killela, PJ, Zhang, J, Wu, Z, Li, G, Hao, S, Wang, Y, Webb, JB, Friedman, HS, Friedman, AH, McLendon, RE, He, Y, Reitman, ZJ, Bigner, DD & Yan, H 2014, 'Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas', Nature Genetics, vol. 46, no. 7, pp. 726-730. https://doi.org/10.1038/ng.2995

TY - JOUR

T1 - Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

AU - Zhang, Liwei

AU - Chen, Lee H.

AU - Wan, Hong

AU - Yang, Rui

AU - Wang, Zhaohui

AU - Feng, Jie

AU - Yang, Shaohua

AU - Jones, Siân

AU - Wang, Sizhen

AU - Zhou, Weixin

AU - Zhu, Huishan

AU - Killela, Patrick J.

AU - Zhang, Junting

AU - Wu, Zhen

AU - Li, Guilin

AU - Hao, Shuyu

AU - Wang, Yu

AU - Webb, Joseph B.

AU - Friedman, Henry S.

AU - Friedman, Allan H.

AU - McLendon, Roger E.

AU - He, Yiping

AU - Reitman, Zachary J.

AU - Bigner, Darell D.

AU - Yan, Hai

N1 - Funding Information: This study was partly supported by National Cancer Institute grant R01CA140316 (H.Y.), the American Cancer Society (RSG-10-126-01-CCE) (H.Y.), a Pediatric Brain Tumor Foundation Institute grant (D.D.B.), a Voices Against Brain Cancer Foundation grant (D.D.B.), a James S. McDonnell Foundation grant (H.Y.), The V Foundation (H.Y.), an Accelerate Brain Cancer Cure Foundation grant (H.Y.), a Pediatric Brain Tumor Foundation Institute at Duke Early Career Award (Z.J.R.) and Natural Science Foundation of China grants 30772237 and 81241078 (L.Z.).

PY - 2014/7

Y1 - 2014/7

N2 - Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

AB - Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

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U2 - 10.1038/ng.2995

DO - 10.1038/ng.2995

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VL - 46

SP - 726

EP - 730

JO - Nature Genetics

JF - Nature Genetics

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ER -

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

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