弥漫性神经胶质瘤是一种高度异质性的中枢神经系统肿瘤,对常规治疗难以治疗。残余的胶质瘤细胞从手术和放化疗中逃逸,导致致命的复发。了解这种复发过程的分子机制对于开发成功的疗法至关重要。这里,我们通过一个统一的管道分析了来自46例神经胶质瘤患者的97个配对的原发和复发样本的全外显子组测序(WES)数据.克隆性和系统发育分析表明,分支进化在神经胶质瘤的复发过程中普遍存在。复发性肿瘤继续通过放化疗独立进化,并具有多种复发选择的遗传改变。如PPFIBP1,PDE4DIP的扩增,还有KRAS,TNFRSF14,DCC,CDKN2A,和MSH6,以及ATRX的突变,ARID1A,KEL,TP53、MSH6和KMT2B。同时,在原发性和复发性神经胶质瘤中鉴定出部分驱动基因内的躯干变异,表明它们可能是理想的治疗目标。有趣的是,与原发性肿瘤相比,复发性胶质瘤的免疫原性没有显著增加.复发性神经胶质瘤的基因组分析提供了鉴定在临床采样的原发性肿瘤中未检测到的潜在临床信息改变的机会。
Diffuse glioma is a highly heterogeneous central nervous system tumor that is refractory to conventional therapy. Residual glioma cells escape from surgery and chemoradiotherapy, leading to lethal recurrence. Understanding the molecular mechanism of this recurrence process is critical to the development of successful therapies. Here, we analyzed whole-exome sequencing (WES) data of 97 paired primary and recurrent samples from 46 patients with glioma via a uniform pipeline. Clonality and phylogenetic analyses revealed that branching evolution was widespread in the recurrent process of gliomas. Recurrent tumors continued to evolve independently with chemoradiotherapy and harbored multiple recurrence-selected genetic alterations, such as amplification of PPFIBP1, PDE4DIP, and KRAS, deletion of TNFRSF14, DCC, CDKN2A, and MSH6, and mutations in ATRX, ARID1A, KEL, TP53, MSH6, and KMT2B. Meanwhile, truncal variants within partial driver genes were identified among primary and recurrent gliomas, suggesting that they might be ideal therapeutic targets. Intriguingly, the immunogenicity of recurrent gliomas did not increase significantly compared to the primary tumors. Genomic analysis of recurrent gliomas provided an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors.