Abstract：
Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.
摘要：
尽管已经对胶质母细胞瘤（GBM）的基因组异常进行了十多年的研究，5年生存率低于5%。我们寻求扩大高级别神经胶质瘤的分子景观，由IDH野生型GBM和IDH突变型4级星形细胞瘤组成，通过整合蛋白质组学，代谢组学，脂质体，和翻译后修饰（PTM）与基因组和转录组测量揭示控制肿瘤发展和进化的多尺度调控相互作用。将14个蛋白质基因组和代谢组学平台应用于228个肿瘤（212GBM和16个4级IDH突变型星形细胞瘤），包括复发时的28，加上18个正常脑样本和14个脑转移瘤作为比较，揭示了在蛋白质组和代谢组水平上聚集在常见下游事件上的异质上游改变，以及在复发时蛋白质-蛋白质相互作用和糖基化位点占据的变化。PTPN11上的反复遗传改变和磷酸化事件在三个维度上映射到重要的调节域，提示PTPN11信号在高级别神经胶质瘤中的重要作用。
