Homo sapiens Exome

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. 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.

起源于脑干与丘脑的胶质瘤是一类恶性程度极高、手术全切难度极大的致死性肿瘤。为明确此类肿瘤的遗传与表观遗传图谱，本研究对14例脑干胶质瘤（BSGs）及12例丘脑胶质瘤开展了外显子组测序。本研究在37.5%携带标志性H3F3A突变（编码p.Lys27Met替换）的脑干胶质瘤中，发现了PPM1D基因的肿瘤特异性突变，该基因编码野生型p53诱导蛋白磷酸酶1D（WIP1）。在脑干胶质瘤中，PPM1D突变与TP53突变呈互斥关系，且可在体外实验中削弱p53的激活活性。PPM1D突变为外显子6区域的截短突变，该突变可增强PPM1D对DNA损伤应答检查点蛋白CHK2激活的抑制能力。上述研究结果明确了PPM1D是脑干胶质瘤中体细胞突变的高频靶标，同时也是潜在的治疗靶点。