DNA secondary structures and epigenetic determinants of cancer genome evolution
DNA secondary structures and epigenetic determinants of cancer genome evolution
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DOI：
10.1038/nsmb.2089
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发表时间：
2011-08-01
影响因子：
16.8
通讯作者：
Michor, Franziska
中科院分区：
文献类型：
--
作者：
De, Subhajyoti;Michor, Franziska
不稳定的基因组是许多癌症的标志。然而，目前尚不清楚是否有一些突变特征驱动癌症的体细胞改变是在基因组序列中编码的，以及它们是否可以以组织特异性的方式运作。我们对来自2,792个癌症样本（分为26种癌症类型）的663,446个与体细胞拷贝数改变（SCNA）相关的DNA断裂点进行了全基因组分析。许多SCNA断裂点在癌症基因组中空间聚集。我们观察到一个显着的富集G-四链体序列（G4）在附近的SCNA断点，并建立SCNAs显示与G4介导的结构改变一致的链偏差。值得注意的是，在富含G4的区域附近的异常低甲基化是许多SCNA断裂点热点的常见特征。我们提出了一个机制假说，即在富含G4的基因组区域中的异常低甲基化作为一种诱变因素，驱动癌症中的组织特异性突变景观。
An unstable genome is a hallmark of many cancers. It is unclear, however, whether some mutagenic features driving somatic alterations in cancer are encoded in the genome sequence and whether they can operate in a tissue-specific manner. We performed a genome-wide analysis of 663,446 DNA breakpoints associated with somatic copy-number alterations (SCNAs) from 2,792 cancer samples classified into 26 cancer types. Many SCNA breakpoints are spatially clustered in cancer genomes. We observed a significant enrichment for G-quadruplex sequences (G4s) in the vicinity of SCNA breakpoints and established that SCNAs show a strand bias consistent with G4-mediated structural alterations. Notably, abnormal hypomethylation near G4s-rich regions is a common signature for many SCNA breakpoint hotspots. We propose a mechanistic hypothesis that abnormal hypomethylation in genomic regions enriched for G4s acts as a mutagenic factor driving tissue-specific mutational landscapes in cancer.