Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma
Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma
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DOI：
10.1038/s41588-019-0547-z
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发表时间：
2020-01-01
期刊：
影响因子：
30.8
通讯作者：
Henssen, Anton G.
中科院分区：
文献类型：
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作者：
Koche, Richard P.;Rodriguez-Fos, Elias;Henssen, Anton G.
DNA 染色体外环化是癌症中一个重要的基因组特征。然而，染色体外环状 DNA 的结构、组成和全基因组频率尚未得到广泛研究。在这里，我们结合基因组学和转录组学方法来描述神经母细胞瘤中染色体外环状 DNA 的情况，神经母细胞瘤是一种在儿童时期由交感神经系统原始细胞产生的肿瘤。我们的分析鉴定并表征了一系列体细胞获得的和未描述的染色体外环状 DNA。此外，我们发现染色体外环状DNA是体细胞重排的一个意想不到的主要来源，通过嵌合环化和环状DNA重新整合到线性基因组中，有助于致癌重塑。致癌病变可能是由环衍生的重排产生的，并与不良的临床结果相关。环衍生的重排很可能代表持续的诱变过程。因此，染色体外环状DNA代表了多重突变过程，对癌症基因组重塑的起源具有重要的功能和临床意义。基因组学和转录组学相结合的方法确定了神经母细胞瘤中染色体外环状DNA的情况，并揭示了染色体外环状DNA是体细胞重排的主要来源。
Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.Combined genomic and transcriptomic approaches identify the landscape of extrachromosomal circular DNA in neuroblastoma and reveal that extrachromosomal circular DNA is a major source of somatic rearrangements.