Cho Sung-Yup, Park Changho, Na Deukchae, Han Jee Yun, Lee Jieun, Park Ok-Kyoung, Zhang Chengsheng, Sung Chang Ohk, Moon Hyo Eun, Kim Yona, Kim Jeong Hoon, Kim Jong Jae, Khang Shin Kwang, Nam Do-Hyun, Choi Jung Won, Suh Yeon-Lim, Kim Dong Gyu, Park Sung Hye, Youn Hyewon, Yun Kyuson, Kim Jong-Il, Lee Charles, Paek Sun Ha, Park Hansoo
Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Exp Mol Med. 2017 Apr 14;49(4):e317. doi: 10.1038/emm.2017.9.
Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87-199.63, P=0.003). A pathway analysis showed recurrent alterations in MAPK signaling (EGFR, RASGRF2 and TP53), phosphatidylinositol/calcium signaling (CACNA1s, PLCs and ITPRs) and focal adhesion/tight junction (PTEN and PAK3) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial-mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS.
胶质肉瘤（GS）是胶质母细胞瘤（GBM）的一种罕见变体（2%），由于其预后较差且基因组信息有限，给临床基因组学带来了挑战。为了全面了解GS中的基因组改变并理解GS的分子病因，我们对28例GS病例进行了全外显子测序分析（6例血液匹配的新鲜冷冻组织用于发现集，22例福尔马林固定石蜡包埋组织用于验证集），并对5例血液匹配的新鲜冷冻组织进行了拷贝数变异微阵列分析。与GBM病例（29/90，32%）相比，TP53突变在GS病例中更为普遍（20/28，70%），并且具有TP53突变的GS患者生存期明显更短（多变量Cox分析，风险比=23.9，95%置信区间，2.87 - 199.63，P = 0.003）。通路分析显示丝裂原活化蛋白激酶信号通路（EGFR、RASGRF2和TP53）、磷脂酰肌醇/钙信号通路（CACNA1s、PLCs和ITPRs）以及粘着斑/紧密连接通路（PTEN和PAK3）存在反复改变。对匹配的复发性GS病例进行基因组分析，在两例复发性GS病例中检测到TP53突变的发生，这表明TP53突变在治疗耐药中起作用。在功能上，我们发现TP53突变与GS肉瘤成分的上皮-间质转化（EMT）过程相关。我们提供了首个全面的GS全基因组遗传改变图谱，这表明基于TP53突变状态可在GS患者中划分出新的预后亚组，并为GS的发病机制和靶向治疗提供了新的见解。
