PDF(Pubmed)
Abstract：
The study of extrachromosomal DNA (ecDNA), an element existing beyond classical chromosomes, contributes to creating a more comprehensive map of the cancer genome. In hematological malignancies, research on ecDNA has lacked comprehensive investigation into its frequency, structure, function, and mechanisms of formation. We re-analyzed WGS data from 208 hematological cancer samples across 11 types, focusing on ecDNA characteristics. Amplification of ecDNA was observed in 7 of these cancer types, with no instances found in normal blood cells. Patients with leukemia carrying ecDNA showed a low induction therapy remission rate (<30 %), a high relapse rate (75 %) among those who achieved complete remission, and a significantly lower survival rate compared to the general leukemia population, even those with complex chromosomal karyotypes. Among the 55 identified ecDNA amplicons, 268 genes were detected, of which 38 are known cancer-related genes exhibiting significantly increased copy numbers. By integrating RNA-Seq data, we discovered that the increased copy number, resulting in a higher amount of available DNA templates, indeed leads to the elevated expression of genes encoded on ecDNA. Additionally, through the integration of H3K4me3/H3K27ac chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin with sequencing, and high-throughput chromosome conformation capture data, we identified that ecDNA amplifications can also facilitate efficient, copy number-independent amplification of oncogenes. This process is linked to active histone modifications, improved chromatin accessibility, and enhancer hijacking, all of which are effects of ecDNA amplification. Mechanistically, chromothripsis and dysfunction of the DNA repair pathway can, to some extent, explain the origin of ecDNA.
摘要：
染色体外DNA(ecDNA)的研究,存在于经典染色体之外的元素，有助于创建更全面的癌症基因组图。在血液恶性肿瘤中，对ecDNA的研究缺乏对其频率的全面调查，结构,函数,和形成机制。我们重新分析了来自11种类型的208个血液癌症样本的WGS数据，关注ecDNA特征。在7种癌症类型中观察到ecDNA的扩增，在正常血细胞中没有发现任何实例。携带ecDNA的白血病患者显示低诱导治疗缓解率（<30％），在达到完全缓解的患者中，高复发率（75％），与普通白血病人群相比，存活率明显较低，甚至那些具有复杂染色体核型的人。在55个鉴定的ecDNA扩增子中，共检测到268个基因，其中38是已知的癌症相关基因，其拷贝数显着增加。通过整合RNA-Seq数据,我们发现拷贝数的增加，导致更多的可用DNA模板，确实导致ecDNA上编码的基因表达升高。此外,通过整合H3K4me3/H3K27ac染色质免疫沉淀测序，用测序测定转座酶可接近的染色质，和高通量染色体构象捕获数据，我们发现ecDNA扩增也可以促进高效，癌基因的拷贝数无关扩增。这个过程与活跃的组蛋白修饰有关，改善染色质可及性，增强剂劫持，所有这些都是ecDNA扩增的影响。机械上,染色体增生和DNA修复途径的功能障碍，在某种程度上,解释ecDNA的起源。
