APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions.
APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions.
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DOI：
10.1016/j.celrep.2015.09.077
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发表时间：
2015-11-10
期刊：
影响因子：
8.8
通讯作者：
Sunyaev SR
中科院分区：
文献类型：
--
作者：
Kazanov MD;Roberts SA;Polak P;Stamatoyannopoulos J;Klimczak LJ;Gordenin DA;Sunyaev SR
人类先天免疫系统的一种抗病毒成分——载脂蛋白B mRNA编辑酶催化多肽样（APOBEC）胞苷脱氨酶，最近被确定为癌症中突变的一个重要来源。在此，我们研究了119例乳腺癌和24例肺癌样本基因组中APOBEC诱导的突变分布情况。虽然已知大多数突变率在以染色质可及性降低和基因密度低为特征的晚期复制区域升高，但我们观察到APOBEC突变在早期复制区域显著富集。这种不寻常的突变特征可能与早期复制区域更易形成APOBEC酶的单链DNA底物有关，并且在旨在了解癌症发生机制以及突出癌症中显著突变基因的癌症基因组突变目录的统计分析中应予以考虑。
An antiviral component of the human innate immune system - the APOBEC cytidine deaminases – was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogues aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer.