• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>NPJ Precision Oncology >Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens
【2h】

Resolving the phylogenetic origin of glioblastoma via multifocal genomic analysis of pre-treatment and treatment-resistant autopsy specimens

机译：通过对治疗前和治疗后的尸体标本进行多焦点基因组分析来解决胶质母细胞瘤的系统起源

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Glioblastomas are malignant neoplasms composed of diverse cell populations. This intratumoral diversity has an underlying architecture, with a hierarchical relationship through clonal evolution from a common ancestor. Therapies are limited by emergence of resistant subclones from this phylogenetic reservoir. To characterize this clonal ancestral origin of recurrent tumors, we determined phylogenetic relationships using whole exome sequencing of pre-treatment IDH1/2 wild-type glioblastoma specimens, matched to post-treatment autopsy samples (n = 9) and metastatic extracranial post-treatment autopsy samples (n = 3). We identified “truncal” genetic events common to the evolutionary ancestry of the initial specimen and later recurrences, thereby inferring the identity of the precursor cell population. Mutations were identified in a subset of cases in known glioblastoma genes such as NF1(n = 3), TP53(n = 4) and EGFR(n = 5). However, by phylogenetic analysis, there were no protein-coding mutations as recurrent truncal events across the majority of cases. In contrast, whole copy-loss of chromosome 10 (12 of 12 cases), copy-loss of chromosome 9p21 (11 of 12 cases) and copy-gain in chromosome 7 (10 of 12 cases) were identified as shared events in the majority of cases. Strikingly, mutations in the TERT promoter were also identified as shared events in all evaluated pairs (9 of 9). Thus, we define four truncal non-coding genomic alterations that represent early genomic events in gliomagenesis, that identify the persistent cellular reservoir from which glioblastoma recurrences emerge. Therapies to target these key early genomic events are needed. These findings offer an evolutionary explanation for why precision therapies that target protein-coding mutations lack efficacy in GBM.
机译：胶质母细胞瘤是由不同细胞群体组成的恶性肿瘤。这种肿瘤内的多样性具有潜在的结构，通过从共同祖先的克隆进化而具有等级关系。从该系统发育库中出现抗性亚克隆限制了治疗。为了表征复发性肿瘤的这种克隆祖先起源，我们使用治疗前IDH1 / 2野生型胶质母细胞瘤标本的全外显子组测序，与治疗后尸检样本（n = 9）和转移性颅外治疗后尸检相匹配，确定了系统发生关系。样本（n = 3）。我们确定了原始样本的进化祖先和后来的复发所共有的“截断”遗传事件，从而推断出前体细胞群体的身份。在已知的胶质母细胞瘤基因如NF1（n = 3），TP53（n = 4）和EGFR（n = 5）的部分病例中鉴定出突变。但是，通过系统发育分析，在大多数情况下，没有蛋白质编码突变作为复发性截断事件。相比之下，在大多数情况下，第10号染色体的整体复制损失（12例中的12例），9p21号染色体的复制损失（12例中的11例）和第7号染色体的复制增益（12例中的10例）被确定为共享事件的情况。令人惊讶的是，TERT启动子中的突变也被鉴定为所有评估对中的共享事件（9个中的9个）。因此，我们定义了四个截短的非编码基因组改变，它们代表神经胶质瘤发生中的早期基因组事件，它们确定了胶质母细胞瘤复发的持久性细胞库。需要针对这些关键的早期基因组事件的疗法。这些发现为为什么靶向蛋白质编码突变的精密疗法为何在GBM中缺乏疗效提供了进化的解释。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号