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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.
(ProQuest: ... denotes formulae omitted.)
Genome instability triggers the development of many types of cancers1,2. Radiation and chemical damage are traditionally invoked as culprits in theories of carcinogenic mutagenesis3. However, normal enzymatic activities can also be a source of DNA damage and mutation. Cytidine deaminases, which convert cytosine bases to uracil, likely contribute to DNA damage4. Activation-induced cytidine deaminase (AID), a key enzyme in adaptive immunity, not only initiates the hypermutation and class-switch recombination of immunoglobulin genes but also can mutate chromosomal DNA at a limited number of secondary targets, some of which have been implicated in carcinogenesis5. In addition to AID, the human genome encodes several homologous APOBEC (apolipoprotein B mRNA- editing enzyme, catalytic polypeptide-like) cytidine deaminases that function in innate immunity as well as in RNA editing6. Previous human cell culture studies showed that a subclass of APOBECs with mutational specificity for TC motifs (with the mutated base underlined) is capable of inducing mutations in chromosomal and mitochondrial DNA and therefore could have a role in carcinogenesis7-9. (APOBEC without the gene-specifying suffix is used hereafter to designate a subclass of cytidine deaminases with TC motif specificity. Note that, on the basis of motif specificity, APOBEC3G and AID do not fall into this subclass.) Supporting a role for APOBECs in cancer, a mutation signature consistent with...