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首页> 外文学位 >Evolution of low-grade glioma through intratumoral heterogeneity of the genome and epigenome.
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Evolution of low-grade glioma through intratumoral heterogeneity of the genome and epigenome.

机译：低级神经胶质瘤通过基因组和表观基因组的肿瘤内异质性进化。

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摘要

Low-grade glioma (LGG) is a diffuse and infiltrative adult brain tumor. Due to the invasive nature of the tumor, surgical resection is rarely curative. LGG often undergo malignant progression and recur as a high-grade glioblastoma (GBM). The genomic and epigenomic landscapes of these tumors, particularly at recurrence, are understudied yet clinically important. Recurrent tumors may be driven by a distinct set of genetic and epigenetic alterations than their initial tumors, yet therapeutic decisions are often made based on profiling of initial malignancies. Here we comprehensively profiled 33 LGGs and their patient-matched recurrences, including cases with 2-6 intratumoral samples, with exome sequencing to identify somatic mutations, with the Infinium 450K array to investigate DNA methylation changes, and with RNA sequencing to measure gene expression changes. We found a wide range in the degree of evolution from initial to recurrence, in terms of both somatic mutations and DNA methylation changes. Tumors treated with the alkylating chemotherapy temozolomide (TMZ) often recurred with a hypermutation phenotype that was suggestive of therapy-driven malignant progression to GBM. Therapy-associated mutational activation of the AKT-mTOR pathway was a consistent feature of these hypermutated recurrences, which promoted a new clinical trial combining the anti-tumor activity of TMZ with an mTOR inhibitor. Recurrence as GBM was associated with aberrations to cell cycle genes through convergence of both genetic and epigenetic mechanisms. Moreover, we found that the evolutionary history of a tumor is similar whether inferred from genetic or epigenetic data, suggesting co-evolution of the genome and epigenome. Finally, we identified cases in which mutations in IDH1, which are the earliest known alteration in LGG and drive gliomagenesis, were either deleted or amplified at recurrence. Mutant IDH1 reprograms the epigenome and these recurrences showed partial reversion of these epigenomic alterations. Together, these findings highlight the heterogeneity and continual evolution of LGG and emphasize the importance of studying recurrent tumors for a more complete understanding of tumor evolution and to make more informed treatment decisions.
机译：低度神经胶质瘤（LGG）是一种弥漫性浸润性成人脑肿瘤。由于肿瘤的侵袭性，手术切除很少能治愈。 LGG经常经历恶性进展并复发为高级别胶质母细胞瘤（GBM）。这些肿瘤的基因组和表观基因组情况，特别是复发时，尚未得到充分研究，但在临床上很重要。复发性肿瘤可能是由与原始肿瘤不同的一组遗传和表观遗传学改变驱动的，但是治疗决策通常是基于对初始恶性肿瘤的分析而做出的。在这里，我们全面分析了33种LGG及其与患者匹配的复发情况，包括2-6例肿瘤内样本的病例，外显子组测序以识别体细胞突变，Infinium 450K阵列研究DNA甲基化变化以及RNA测序以测量基因表达变化。 。我们发现从体细胞突变和DNA甲基化变化而言，从最初到复发的进化程度范围很广。用烷基化化疗替莫唑胺（TMZ）治疗的肿瘤通常会复发，表现为高突变表型，提示治疗导致恶性进展为GBM。 AKT-mTOR途径的与治疗相关的突变激活是这些高突变复发的一致特征，从而促进了一项结合TMZ与mTOR抑制剂的抗肿瘤活性的新临床试验。由于GBM的复发与遗传和表观遗传机制的趋同与细胞周期基因的畸变有关。此外，我们发现无论是从遗传数据还是从表观遗传学数据推断，肿瘤的进化史都是相似的，这表明基因组和表观基因组共同进化。最后，我们确定了IDH1突变（这是LGG中最早的已知突变并驱动神经胶质瘤的发生）在复发时被删除或扩增的病例。突变IDH1重新编程了表观基因组，这些复发表明这些表观基因组改变部分逆转。总之，这些发现突出了LGG的异质性和持续进化，并强调了研究复发性肿瘤以更全面地了解肿瘤进化并做出更明智的治疗决策的重要性。

著录项

  • 作者

    Mazor, Tali.;

  • 作者单位

    University of California, San Francisco.;

  • 授予单位 University of California, San Francisco.;
  • 学科 Biology.;Oncology.;Genetics.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 165 p.
  • 总页数 165
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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