Comprehensive molecular characterization of long-term glioblastoma survivors

作者：Hao Xu, Xinyu Chen, Ying Sun, Xiaomu Hu, Xuan Zhang, Ye Wang, Qisheng Tang, Qiongji Zhu, Kun Song, Hong Chen, Xiaofang Sheng, Yu Yao, Dongxiao Zhuang, Lingchao Chen, Ying Mao, Zhiyong Qin · 发表于：Cancer Letters · 年份：2024 · DOI：10.1016/j.canlet.2024.216938 · 被引用次数：14 · 研究领域：Glioma Diagnosis and Treatment、Mitochondrial Function and Pathology、Cancer, Hypoxia, and Metabolism

Fewer than 5% glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4+ T cells (P = 0.031) and CD4+ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8% of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS coul...