Abstract
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.
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Acknowledgements
We would like to thank J. Taylor, P. Wade and D. Zaykin for helpful discussions and critical reading of the manuscript. The results published here are in part based on data generated by the TCGA project established by the National Cancer Institute and the National Human Genome Research Institute (database of Genotypes and Phenotypes (dbGaP) accession phs000178.v8.p7). The work was supported in part by the Intramural Research Program of the US National Institutes of Health, the National Institute of Environmental Health Sciences (project ES065073 to M.A.R.; contract GS-23F-9806H and order HHSN273201000086U to R.R.S.) and by the National Human Genome Research Institute (grant U54HG003067 to G.G.).
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S.A.R., G.G. and D.A.G. designed the study. S.A.R., M.S.L., L.J.K., S.A.G., D.F., P.S., A.K., G.V.K., S.L.C., G.S., S.H., R.R.S., M.A.R., G.G. and D.A.G. contributed to data analysis. S.A.R. and D.A.G. wrote the manuscript.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–14 and Supplementary Table 3 (PDF 4520 kb)
Supplementary Table 1
Summary of mutagenesis in 21 whole genome–sequenced human breast cancers (XLSX 56 kb)
Supplementary Table 2
Mutation clusters in 9 whole genome–sequenced colorectal adenocarcinomas (XLSX 538 kb)
Supplementary Table 4
Summary of mutagenesis, APOBEC expression and segmental CNVs in human cancer exomes (XLSX 2595 kb)
Supplementary Table 5
Occurrences of APOBEC and non-APOBEC driver mutations in 2,680 cancer exomes (XLSX 689 kb)
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Roberts, S., Lawrence, M., Klimczak, L. et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nat Genet 45, 970–976 (2013). https://doi.org/10.1038/ng.2702
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DOI: https://doi.org/10.1038/ng.2702
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