@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",
}