Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.
Nat Genet. 2013 Sep;45(9):970-6. doi: 10.1038/ng.2702. Epub 2013 Jul 14.
Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic.
最近的研究表明，APOBEC 胞嘧啶脱氨酶的一个亚类在 RNA 编辑和逆转录病毒或 retrotransposon 限制过程中将胞嘧啶转化为尿嘧啶，可能在人类肿瘤中诱导突变簇。我们在这里表明，在整个癌症基因组中，APOBEC 介导的诱变是普遍存在的，并与 APOBEC mRNA 水平相关。全基因组和外显子组数据集中的突变簇符合严格的标准，表明存在 APOBEC 突变模式。将这些标准应用于来自 14 种癌症类型（主要来自癌症基因组图谱 (TCGA)）的 2680 个外显子中的 954247 个突变，显示在膀胱癌、宫颈癌、乳腺癌、头颈部癌和肺癌中存在明显的 APOBEC 突变模式，在某些样本中达到所有突变的 68%。在乳腺癌中，HER2 富集亚型的肿瘤明显富含 APOBEC 突变模式，表明这种类型的诱变与癌症发展具有功能联系。APOBEC 突变模式也扩展到癌症相关基因，暗示普遍存在的 APOBEC 介导的诱变是致癌的。
