An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers.
An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers.
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DOI：
10.1038/ng.3378
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发表时间：
2015-09
期刊：
影响因子：
30.8
通讯作者：
Gordenin DA
中科院分区：
文献类型：
--
作者：
Chan K;Roberts SA;Klimczak LJ;Sterling JF;Saini N;Malc EP;Kim J;Kwiatkowski DJ;Fargo DC;Mieczkowski PA;Getz G;Gordenin DA
阐明形成癌症基因组的诱变过程是一个基本问题，其解决方案有望洞察新的治疗，诊断和预防策略。单链DNA特异性APOBEC胞苷脱氨酶是几种癌症类型中突变的主要来源。先前的间接证据表明APOBEC3B更可能是主要的增变脱氨酶，而APOBEC3A的作用尚未确定。使用酵母模型，使长单链基因组DNA底物的控制生成，我们表明，APOBEC3A和APOBEC3B的突变签名是统计上可区分的。然后，我们应用三种互补方法来识别具有类似于APOBEC的突变特征的癌症样本。引人注目的是，APOBEC3A样样品比APOBEC3B样样品具有超过十倍的APOBEC特征突变。我们认为，APOBEC3A介导的诱变更为频繁，因为APOBEC3A本身非常擅长产生DNA断裂，其修复可以触发单链超突变底物的形成。
Elucidation of mutagenic processes shaping cancer genomes is a fundamental problem whose solution promises insights into new treatment, diagnostic and prevention strategies. Single-strand DNA–specific APOBEC cytidine deaminase(s) are major source(s) of mutation in several cancer types,,. Previous indirect evidence implicated APOBEC3B as the more likely major mutator deaminase, whereas the role of APOBEC3A is not established,. Using yeast models enabling the controlled generation of long single-strand genomic DNA substrates, we show that the mutation signatures of APOBEC3A and APOBEC3B are statistically distinguishable. We then apply three complementary approaches to identify cancer samples with mutation signatures resembling either APOBEC. Strikingly, APOBEC3A-like samples have over tenfold more APOBEC-signature mutations than APOBEC3B-like samples. We propose that APOBEC3A-mediated mutagenesis is much more frequent because APOBEC3A itself is highly proficient at generating DNA breaks,,, whose repair can trigger the formation of single-strand hypermutation substrates.