胶质母细胞瘤（GBM）是成人中最常见的致命性原发性脑癌。尽管治疗方案包括手术切除、放疗和替莫唑胺（TMZ）化疗，但残留肿瘤的生长会导致治疗抵抗和死亡。在复发时，四分之一到三分之一的神经胶质瘤具有高度突变的基因组，其突变负担比正常组织大几个数量级。在这里，我们量化了患者原发性和复发性 GBM 中的突变景观进展，并发现了 Cas9 可靶向的重复元件。我们证明，CRISPR 介导的高度重复基因座的靶向能够快速消除 GBM 细胞，我们将这种方法称为“基因组粉碎”。重要的是，在患者的复发性 GBM 中，我们鉴定了具有 TMZ 突变特征的独特重复序列，并证明其 CRISPR 靶向能够实现癌症特异性细胞消融。 “癌症粉碎”利用非编码基因组和治疗诱导的突变特征来靶向 GBM 细胞耗竭，并提供了开发高突变神经胶质瘤治疗方法的创新范例。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Glioblastoma (GBM) is the most common lethal primary brain cancer in adults. Despite treatment regimens including surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy, growth of residual tumor leads to therapy resistance and death. At recurrence, a quarter to a third of all gliomas have hypermutated genomes, with mutational burdens orders of magnitude greater than in normal tissue. Here, we quantified the mutational landscape progression in a patient's primary and recurrent GBM, and we uncovered Cas9-targetable repeat elements. We show that CRISPR-mediated targeting of highly repetitive loci enables rapid elimination of GBM cells, an approach we term "genome shredding." Importantly, in the patient's recurrent GBM, we identified unique repeat sequences with TMZ mutational signature and demonstrated that their CRISPR targeting enables cancer-specific cell ablation. "Cancer shredding" leverages the non-coding genome and therapy-induced mutational signatures for targeted GBM cell depletion and provides an innovative paradigm to develop treatments for hypermutated glioma.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.