Zhong Sheng, Wu Bo, Dubois Frank, Deng Davy, Bergholz Johann S, Hu Wanming, Duan Hao, Shao Yujie, Liu Jingyi, Liu Luwei, Chen Sitong, Hu Yongfei, Zhao Zheng, Yao Maojin, Sai Ke, Wang Jian, Chen Yinsheng, Ke Chao, Zhang Xiangheng, Yang Qunying, Guo Chengcheng, Zhang Ji, Lin Fuhua, Chen Zhenghe, Li Deipei, He Zhenqiang, Li Chang, Jiang Xiaobing, Lu Jie, Yang Wenzhuo, Jiang Tao, Chen Zhongping, Beroukhim Rameen, Zhao Jean J, Mou Yonggao
Department of Neurosurgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China; Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Lower Extremity Division, Orthopedic Trauma Department, Honghui Hospital, Xi'an Jiaotong University, Xi'an, China.
Cell Rep Med. 2025 Aug 19;6(8):102217. doi: 10.1016/j.xcrm.2025.102217.
Glioblastoma multiforme (GBM) shows profound inter- and intratumoral heterogeneity, but differences across ancestries remain understudied. We assemble the largest cohort of GBMs from East Asian patients (EAS-GBM) and perform genomic and transcriptomic analyses. Transcriptomic clustering reveals distinct EAS-GBM molecular subtypes-proliferative (PL), neurosynaptic (NS), metabolic (MB), and immunomodulatory (IM)-based on activated biological pathways. We also identify protein markers enabling subtype classification in pathology. Comparative analysis with the predominantly European-ancestry The Cancer Genome Atlas (TCGA) GBM dataset (EUR-GBM) reveals similar main drivers, though EAS-GBMs lack the epidermal growth factor receptor (EGFR)-defined classical EUR-GBM subtype. EAS PL-GBMs display CCNE1/CCND2 overexpression, with myelocytomatosis viral oncogene (MYC) signaling activation. The IM-GBM cluster exhibits an immunotherapy-responsive expression profile, corroborated by improved overall survival under immune checkpoint blockade in an external dataset. Together, our data reveal distinctive genomic features of EAS-GBMs that may inform patient stratification for targeted therapy and drug development tailored to the EAS population.
多形性胶质母细胞瘤（GBM）表现出显著的肿瘤间和肿瘤内异质性，但不同种族之间的差异仍未得到充分研究。我们汇集了来自东亚患者的最大规模GBM队列（EAS-GBM），并进行了基因组和转录组分析。转录组聚类揭示了基于激活的生物途径的不同EAS-GBM分子亚型——增殖型（PL）、神经突触型（NS）、代谢型（MB）和免疫调节型（IM）。我们还确定了能够在病理学中进行亚型分类的蛋白质标志物。与主要为欧洲血统的癌症基因组图谱（TCGA）GBM数据集（EUR-GBM）的比较分析显示，主要驱动因素相似，尽管EAS-GBM缺乏表皮生长因子受体（EGFR）定义的经典EUR-GBM亚型。EAS PL-GBM表现出CCNE1/CCND2过表达，并伴有髓细胞瘤病毒癌基因（MYC）信号激活。IM-GBM簇表现出免疫治疗反应性表达谱，外部数据集中免疫检查点阻断下总体生存率的提高证实了这一点。总之，我们的数据揭示了EAS-GBM独特的基因组特征，这可能为针对EAS人群的靶向治疗和药物开发的患者分层提供信息。
