Zhang Liwei, Chen Lee H, Wan Hong, Yang Rui, Wang Zhaohui, Feng Jie, Yang Shaohua, Jones Siân, Wang Sizhen, Zhou Weixin, Zhu Huishan, Killela Patrick J, Zhang Junting, Wu Zhen, Li Guilin, Hao Shuyu, Wang Yu, Webb Joseph B, Friedman Henry S, Friedman Allan H, McLendon Roger E, He Yiping, Reitman Zachary J, Bigner Darell D, Yan Hai
1] Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. [2].
1] Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center, The Pediatric Brain Tumor Foundation Institute, Durham, North Carolina, USA. [2].
Nat Genet. 2014 Jul;46(7):726-30. doi: 10.1038/ng.2995. Epub 2014 Jun 1.
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.
起源于脑干和丘脑的胶质瘤是难以手术切除的毁灭性肿瘤。为了确定这些肿瘤的遗传和表观遗传特征，我们对14例脑干胶质瘤（BSG）和12例丘脑胶质瘤进行了外显子组测序。我们还对另外24例此类肿瘤进行了靶向突变分析，并对45例胶质瘤进行了全基因组甲基化分析。这项研究发现，在携带编码p.Lys27Met替代的标志性H3F3A突变的37.5%的BSG中，编码野生型p53诱导蛋白磷酸酶1D（WIP1）的PPM1D存在肿瘤特异性突变。PPM1D突变与BSG中的TP53突变相互排斥，并在体外减弱p53激活。PPM1D突变是外显子6中的截短改变，增强了PPM1D抑制DNA损伤反应检查点蛋白CHK2激活的能力。这些结果将PPM1D定义为体细胞突变的常见靶点以及脑干胶质瘤的潜在治疗靶点。
