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首页> 外文学位 >Comprehensive Integrated Genomic and Histopathological Analysis of Paediatric Diffuse Intrinsic Pontine Glioma.
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Comprehensive Integrated Genomic and Histopathological Analysis of Paediatric Diffuse Intrinsic Pontine Glioma.

机译：小儿弥漫性固有性脑桥胶质瘤的综合基因组学和组织病理学分析。

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摘要

Diffuse intrinsic pontine glioma (DIPG) is a devastating, inoperable paediatric brain neoplasm with no effective therapy and near 100% fatality. Diagnosis is based mainly on radiological findings and numerous clinical trials using adjuvant chemotherapy over the last four decades have not shown a survival benefit compared to radiation alone. Although the delicate location of these lesions is a contributing factor to the dismal outcomes seen in these children, most of these clinical trials were designed based on adult protocols, with assumptions that paediatric brainstem tumours, whose histology most often resembles high-grade supratentorial glioblastoma (GBM) of adults, would respond to similar therapies.;By combining histological review, methylation profiling, whole-genome and whole-exome sequencing, gene expression profiling, and copy number analysis of a large cohort of DIPG, we describe differences to adult disease, uncover mutations in novel cancer drivers, histone H3 mutation in 78.5% and ACVR1 mutations in 21.25% of DIPG patients, respectively and discover that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent and MYCN). The H3-K27M subgroup is highly p.Lys27Met histone H3 mutated and associated with additional hits including activating mutations in ACVR1, frequent RB1 and TP53 deletions, PVT-1/MYC or PDGFRA gains/amplifications, genomic instability and alternative lengthening of telomeres. Histone mutations confer a worse overall survival (p = 0.0026). The MYCN subgroup is not associated with histone mutations and is instead characterized by hypermethylation and chromothripsis of chromosome 2p with high-level amplifications of MYCN and ID2. The Silent subgroup affects younger children, has genomes with minimal genomic instability and fewer mutations. Histologically, DIPG represent a spectrum of grade II-IV disease with vast regional differences and frequent leptomeningeal dissemination.;Our results show that this seemingly homogeneous entity in fact comprises three distinct subgroups with different genomic, molecular and histopathological features. This complexity needs to be considered when designing new therapeutic approaches in order to improve outcome for these children.
机译：弥漫性桥脑神经胶质瘤（DIPG）是一种破坏性的，无法手术的小儿脑肿瘤，没有有效的治疗方法，死亡率接近100％。诊断主要基于放射学发现，并且在过去的四十年中，使用辅助化学疗法的大量临床试验均未显示与单纯放射治疗相比有生存优势。尽管这些病变的微妙位置是导致这些儿童不良结局的重要因素，但大多数临床试验都是根据成人方案设计的，并假设小儿脑干肿瘤的组织学特征通常类似于高度的幕上胶质母细胞瘤（ （GBM）的成年人，会对类似的疗法产生反应。；通过结合组织学检查，甲基化分析，全基因组和全外显子测序，基因表达分析以及大量DIPG的拷贝数分析，我们描述了与成人疾病的差异分别发现DIPG患者的新型癌症驱动程序突变，78.5％的组蛋白H3突变和21.25％的ACVR1突变，并发现DIPG是三个分子上不同的亚组（H3-K27M，Silent和MYCN）。 H3-K27M亚组高度p.Lys27Met组蛋白H3突变，并与其他命中有关，包括ACVR1中的激活突变，频繁的RB1和TP53缺失，PVT-1 / MYC或PDGFRA扩增/扩增，基因组不稳定和端粒的延长。组蛋白突变赋予较差的总生存期（p = 0.0026）。 MYCN亚组与组蛋白突变无关，而是以2MY染色体和IDCN2的高水平扩增为特征，其特征在于2p号染色体的甲基化和染色质增高。沉默亚组影响年龄较小的儿童，其基因组具有最小的基因组不稳定性和较少的突变。从组织学上看，DIPG代表了一系列II-IV级疾病，具有巨大的区域差异和频繁的脑膜脑膜散布。在设计新的治疗方法以改善这些儿童的结局时，需要考虑这种复杂性。

著录项

  • 作者

    Buczkowicz, Pawel.;

  • 作者单位

    University of Toronto (Canada).;

  • 授予单位 University of Toronto (Canada).;
  • 学科 Pathology.;Genetics.;Oncology.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 148 p.
  • 总页数 148
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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