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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Hanahan, D. & Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Loeb, L.A. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 51, 3075–3079 (1991).
Luch, A. Nature and nurture—lessons from chemical carcinogenesis. Nat. Rev. Cancer 5, 113–125 (2005).
Conticello, S.G. Creative deaminases, self-inflicted damage, and genome evolution. Ann. NY Acad. Sci. 1267, 79–85 (2012).
Pavri, R. & Nussenzweig, M.C. AID targeting in antibody diversity. Adv. Immunol. 110, 1–26 (2011).
Smith, H.C., Bennett, R.P., Kizilyer, A., McDougall, W.M. & Prohaska, K.M. Functions and regulation of the APOBEC family of proteins. Semin. Cell Dev. Biol. 23, 258–268 (2012).
Suspène, R. et al. Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism. Proc. Natl. Acad. Sci. USA 108, 4858–4863 (2011).
Shinohara, M. et al. APOBEC3B can impair genomic stability by inducing base substitutions in genomic DNA in human cells. Sci. Rep. 2, 806 (2012).
Burns, M.B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366–370 (2013).
Stephens, P. et al. A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat. Genet. 37, 590–592 (2005).
Beale, R.C. et al. Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. J. Mol. Biol. 337, 585–596 (2004).
Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).
Roberts, S.A. et al. Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions. Mol. Cell 46, 424–435 (2012).
Drier, Y. et al. Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability. Genome Res. 23, 228–235 (2013).
Gibbs, P.E. & Lawrence, C.W. Novel mutagenic properties of abasic sites in Saccharomyces cerevisiae. J. Mol. Biol. 251, 229–236 (1995).
Simonelli, V., Narciso, L., Dogliotti, E. & Fortini, P. Base excision repair intermediates are mutagenic in mammalian cells. Nucleic Acids Res. 33, 4404–4411 (2005).
Chan, K. et al. Base damage within single-strand DNA underlies in vivo hypermutability induced by a ubiquitous environmental agent. PLoS Genet. 8, e1003149 (2012).
Senavirathne, G. et al. Single-stranded DNA scanning and deamination by APOBEC3G cytidine deaminase at single molecule resolution. J. Biol. Chem. 287, 15826–15835 (2012).
Chelico, L., Pham, P. & Goodman, M.F. Mechanisms of APOBEC3G-catalyzed processive deamination of deoxycytidine on single-stranded DNA. Nat. Struct. Mol. Biol. 16, 454–455, author reply 455–456 (2009).
Barbieri, C.E. et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat. Genet. 44, 685–689 (2012).
Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).
Bass, A.J. et al. Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion. Nat. Genet. 43, 964–968 (2011).
Shammas, M.A. et al. Dysfunctional homologous recombination mediates genomic instability and progression in myeloma. Blood 113, 2290–2297 (2009).
Liu, P., Carvalho, C.M., Hastings, P.J. & Lupski, J.R. Mechanisms for recurrent and complex human genomic rearrangements. Curr. Opin. Genet. Dev. 22, 211–220 (2012).
TCGA. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
Parker, J.S. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160–1167 (2009).
Landry, S., Narvaiza, I., Linfesty, D.C. & Weitzman, M.D. APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Rep. 12, 444–450 (2011).
Carter, H. et al. Cancer-specific high-throughput annotation of somatic mutations: computational prediction of driver missense mutations. Cancer Res. 69, 6660–6667 (2009).
Douville, C. et al. CRAVAT: Cancer-Related Analysis of VAriants Toolkit. Bioinformatics 29, 647–648 (2013).
Forbes, S.A. et al. The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc. Hum. Genet. Chapter 10, Unit 10.11 (2008).
Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).
Lampson, B.L. et al. Rare codons regulate KRas oncogenesis. Curr. Biol. 23, 70–75 (2012).
Schumacher, A.J., Nissley, D.V. & Harris, R.S. APOBEC3G hypermutates genomic DNA and inhibits Ty1 retrotransposition in yeast. Proc. Natl. Acad. Sci. USA 102, 9854–9859 (2005).
Einav, U. et al. Gene expression analysis reveals a strong signature of an interferon-induced pathway in childhood lymphoblastic leukemia as well as in breast and ovarian cancer. Oncogene 24, 6367–6375 (2005).
Refsland, E.W. et al. Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction. Nucleic Acids Res. 38, 4274–4284 (2010).
Menendez, D., Shatz, M. & Resnick, M.A. Interactions between the tumor suppressor p53 and immune responses. Curr. Opin. Oncol. 25, 85–92 (2013).
Zhou, L. et al. Activation of toll-like receptor-3 induces interferon-λ expression in human neuronal cells. Neuroscience 159, 629–637 (2009).
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr. Eval. Carcinog. Risks Hum. 100, 1–441 (2012).
Lee, E. et al. Landscape of somatic retrotransposition in human cancers. Science 337, 967–971 (2012).
Lopes, M., Foiani, M. & Sogo, J.M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21, 15–27 (2006).
Pagès, V. & Fuchs, R.P. Uncoupling of leading- and lagging-strand DNA replication during lesion bypass in vivo. Science 300, 1300–1303 (2003).
Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–695 (2010).
Bunting, S.F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).
Bando, M. et al. Csm3, Tof1, and Mrc1 form a heterotrimeric mediator complex that associates with DNA replication forks. J. Biol. Chem. 284, 34355–34365 (2009).
Katou, Y. et al. S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424, 1078–1083 (2003).
Yates, L.R. & Campbell, P.J. Evolution of the cancer genome. Nat. Rev. Genet. 13, 795–806 (2012).
Chapman, M.A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).
Berger, M.F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).
Harfe, B.D. & Jinks-Robertson, S. DNA polymerase ζ introduces multiple mutations when bypassing spontaneous DNA damage in Saccharomyces cerevisiae. Mol. Cell 6, 1491–1499 (2000).
Sakamoto, A.N. et al. Mutator alleles of yeast DNA polymerase ζ. DNA Repair (Amst.) 6, 1829–1838 (2007).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate—a practical and powerful approach to multiple testing. J. R. Stat. Soc., B 57, 289–300 (1995).
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.).
The authors declare no competing financial interests.
Supplementary Figures 1–14 and Supplementary Table 3 (PDF 4520 kb)
Summary of mutagenesis in 21 whole genome–sequenced human breast cancers (XLSX 56 kb)
Mutation clusters in 9 whole genome–sequenced colorectal adenocarcinomas (XLSX 538 kb)
Summary of mutagenesis, APOBEC expression and segmental CNVs in human cancer exomes (XLSX 2595 kb)
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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