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首页> 美国卫生研究院文献>Genome Research >Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution
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Architectures of somatic genomic rearrangement in human cancer amplicons at sequence-level resolution

机译：在序列级分辨率下人类癌症扩增子的体细胞基因组重排架构

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摘要

For decades, cytogenetic studies have demonstrated that somatically acquired structural rearrangements of the genome are a common feature of most classes of human cancer. However, the characteristics of these rearrangements at sequence-level resolution have thus far been subject to very limited description. One process that is dependent upon somatic genome rearrangement is gene amplification, a mechanism often exploited by cancer cells to increase copy number and hence expression of dominantly acting cancer genes. The mechanisms underlying gene amplification are complex but must involve chromosome breakage and rejoining. We sequenced 133 different genomic rearrangements identified within four cancer amplicons involving the frequently amplified cancer genes MYC, MYCN, and ERBB2. The observed architectures of rearrangement were diverse and highly distinctive, with evidence for sister chromatid breakage–fusion–bridge cycles, formation and reinsertion of double minutes, and the presence of bizarre clusters of small genomic fragments. There were characteristic features of sequences at the breakage–fusion junctions, indicating roles for nonhomologous end joining and homologous recombination-mediated repair mechanisms together with nontemplated DNA synthesis. Evidence was also found for sequence-dependent variation in susceptibility of the genome to somatic rearrangement. The results therefore provide insights into the DNA breakage and repair processes operative in somatic genome rearrangement and illustrate how the evolutionary histories of individual cancers can be reconstructed from large-scale cancer genome sequencing.
机译：几十年来，细胞遗传学研究表明，体细胞获得的基因组结构重排是大多数人类癌症的共同特征。然而，迄今为止，这些重排在序列级分辨率下的特征仅受到非常有限的描述。依赖于体细胞基因组重排的一个过程是基因扩增，这是癌细胞经常利用的一种机制，可增加拷贝数，从而增加主要发挥作用的癌症基因的表达。基因扩增的基础机制很复杂，但必须涉及染色体断裂和重新结合。我们对涉及频繁扩增的癌症基因MYC，MYCN和ERBB2的四个癌症扩增子中鉴定出的133个不同的基因组重排进行了测序。所观察到的重排结构是多种多样的，并且非常有特色，有姐妹染色单体断裂，融合，桥循环，两分钟的形成和重新插入，以及奇异的小基因组片段簇的存在的证据。断裂-融合连接处的序列具有特征性，表明非同源末端连接和同源重组介导的修复机制以及非模板DNA合成的作用。还发现了基因组对体细胞重排敏感性的序列依赖性变异的证据。因此，结果提供了对在体细胞基因组重排中有效的DNA断裂和修复过程的见解，并说明了如何从大规模癌症基因组测序中重建单个癌症的进化历史。

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