Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.
Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.
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DOI：
10.1016/j.cell.2015.12.050
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发表时间：
2016-01-28
期刊：
影响因子：
64.5
通讯作者：
Getz G
中科院分区：
文献类型：
--
作者：
Haradhvala NJ;Polak P;Stojanov P;Covington KR;Shinbrot E;Hess JM;Rheinbay E;Kim J;Maruvka YE;Braunstein LZ;Kamburov A;Hanawalt PC;Wheeler DA;Koren A;Lawrence MS;Getz G
突变过程不断塑造体细胞基因组，导致免疫、衰老和其他疾病。当癌症是结果时，我们可以通过恶性细胞的克隆扩增来了解这些过程。在这里，我们描述了一个较少探索的癌症突变景观层：两条DNA链之间的突变不对称性。分析来自14种不同癌症类型的590个肿瘤的全基因组序列，我们揭示了诱变过程中广泛存在的不对称性，其中转录（“T类”）不对称性主导UV-，吸烟-和肝癌-相关突变，复制（“R类”）不对称性主导POLE-，APOBEC-和MSI-相关突变。我们报告了一个惊人的现象，转录偶联损伤（TCD）的非转录的DNA链，并提供证据，APOBEC突变发生在DNA复制过程中的滞后链模板。随着越来越多的基因组被测序，研究和分类它们的不对称性将阐明DNA损伤和修复的潜在生物学机制。
Mutational processes constantly shape the somatic genome, leading to immunity, aging, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional (“T-class”) asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations, and replicative (“R-class”) asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of Transcription-Coupled Damage (TCD) on the non-transcribed DNA strand, and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.