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.

中文翻译：

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染色体外环状 DNA 驱动神经母细胞瘤中的致癌基因组重塑。

DNA 的染色体外环化是癌症的重要基因组特征。然而，染色体外环状 DNA 的结构、组成和全基因组频率尚未被广泛分析。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由交感神经系统的原始细胞在儿童时期产生的肿瘤。我们的分析确定并表征了大量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 是体细胞重排的意外主要来源，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。致癌性病变可以从循环衍生的重排中出现，并与不良的临床结果相关。环衍生的重排很可能代表了一个正在进行的诱变过程。因此，染色体外环状 DNA 代表了一个多重突变的诱变过程，对癌症基因组重塑的起源具有重要的功能和临床意义。