Although grading is defined by the highest histological grade observed in a glioma, most high-grade gliomas retain areas with histology reminiscent of their low-grade counterparts. We sought to achieve the following: (i) identify proteins and molecular pathways involved in glioma evolution; and (ii) validate the high mobility group protein B2 (HMGB2) as a key player in tumor progression and as a prognostic/predictive biomarker for diffuse astrocytomas. We performed liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple areas of adult-type astrocytomas and validated our finding in multiplatform-omics studies and high-throughput IHC analysis. LC-MS/MSdetected proteomic signatures characterizing glioma evolution towards higher grades associated with, but not completely dependent, on IDH status. Spatial heterogeneity of diffuse astrocytomas was associated with dysregulation of specific molecular pathways, and HMGB2 was identified as a putative driver of tumor progression, and an early marker of worse overall survival in grades 2 and 3 diffuse gliomas, at least in part regulated by DNA methylation. In grade 4 astrocytomas, HMGB2 expression was strongly associated with proliferative activity and microvascular proliferation. Grounded in proteomic findings, our results showed that HMGB2 expression assessed by IHC detected early signs of tumor progression in grades 2 and 3 astrocytomas, as well as identified GBMs that had a better response to the standard chemoradiation with temozolomide.
尽管胶质瘤的分级依据其组织学最高级别而定，但多数高级别胶质瘤仍保留着具有低级别组织学特征的区域。本研究旨在实现以下目标：(一) 识别参与胶质瘤演化的蛋白质及分子通路；(二) 验证高迁移率族蛋白B2（HMGB2）在肿瘤进展中的关键作用，并确认其作为弥漫性星形细胞瘤预后/预测性生物标志物的价值。我们在成人型星形细胞瘤的多个区域进行液相色谱-串联质谱分析，并通过多组学平台研究及高通量免疫组化分析验证结果。LC-MS/MS检测到表征胶质瘤向更高级别演化的蛋白质组特征，这些特征与IDH状态相关但非完全依赖。弥漫性星形细胞瘤的空间异质性与特定分子通路的失调相关，HMGB2被确认为肿瘤进展的潜在驱动因子，是2级和3级弥漫性胶质瘤总体生存期缩短的早期标志物，其表达至少部分受DNA甲基化调控。在4级星形细胞瘤中，HMGB2表达与增殖活性及微血管增生密切相关。基于蛋白质组学发现，我们的研究结果表明：通过免疫组化评估的HMGB2表达可检测2级和3级星形细胞瘤的早期进展征象，并能识别对替莫唑胺标准放化疗反应更佳的多形性胶质母细胞瘤。
肿瘤(癌症)患者之家