Recurrent Glioblastomas Reveal Molecular Subtypes Associated with Mechanistic Implications of Drug-Resistance

Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6) in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence.既往转录组谱分析（transcriptomic profiling）研究已证实胶质母细胞瘤（glioblastomas）存在明确的分子亚型。另有研究提出，胶质母细胞瘤的复发可通过肿瘤的转录组重编程实现，但其具体特征尚未完全阐明。为深入解析复发性胶质母细胞瘤的分子表型机制，本研究对43例胶质母细胞瘤样本开展了基因表达谱分析，其中包含15例配对的原发-复发样本。无监督聚类分析（unsupervised clustering analyses）结果显示可分为G1与G2两个亚型，分别以增殖相关基因表达特征、神经元样基因表达特征为典型表型。尽管原发肿瘤均归类为G1亚型，但复发性胶质母细胞瘤呈现两种截然不同的表达类型。与配对原发肿瘤相比，G1亚型的复发肿瘤未出现明显的基因表达改变；而G2亚型的复发肿瘤则呈现出从增殖型向神经元样型的表达谱转变。本研究还观察到，G1亚型复发肿瘤中存在干性相关基因的高表达，G2亚型复发肿瘤中则出现DNA修复基因（DNA-repair genes，即AURK、HOX、MGMT及MSH6）的表达异常，上述改变可能以亚型特异性的方式参与肿瘤复发过程中耐药机制的形成。我们推测，复发性胶质母细胞瘤可通过两种不同的转录组重编程策略逃逸化疗药物的杀伤作用。本研究结果可为针对异质性胶质母细胞瘤复发的个性化治疗策略制定提供重要参考依据。