Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Analysis
  • Published:

Evidence for APOBEC3B mutagenesis in multiple human cancers

Nature Genetics volume 45, pages 977–983 (2013)Cite this article

Subjects

Abstract

Thousands of somatic mutations accrue in most human cancers, and their causes are largely unknown. We recently showed that the DNA cytidine deaminase APOBEC3B accounts for up to half of the mutational load in breast carcinomas expressing this enzyme. Here we address whether APOBEC3B is broadly responsible for mutagenesis in multiple tumor types. We analyzed gene expression data and mutation patterns, distributions and loads for 19 different cancer types, with over 4,800 exomes and 1,000,000 somatic mutations. Notably, APOBEC3B is upregulated, and its preferred target sequence is frequently mutated and clustered in at least six distinct cancers: bladder, cervix, lung (adenocarcinoma and squamous cell carcinoma), head and neck, and breast. Interpreting these findings in the light of previous genetic, cellular and biochemical studies, the most parsimonious conclusion from these global analyses is that APOBEC3B-catalyzed genomic uracil lesions are responsible for a large proportion of both dispersed and clustered mutations in multiple distinct cancers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: APOBEC3B is upregulated in numerous cancer types.
Figure 2: Mutation types and signatures in 19 human cancers.
Figure 3: Cytosine mutation spectra for 19 cancers.
Figure 4: APOBEC3B expression levels correlate with total mutation loads and kataegis events.

Similar content being viewed by others

References

  1. 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).

    Article  CAS  Google Scholar 

  2. Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

    Article  CAS  Google Scholar 

  3. Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

    Article  CAS  Google Scholar 

  4. Sjöblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).

    Article  Google Scholar 

  5. Kumar, A. et al. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers. Proc. Natl. Acad. Sci. USA 108, 17087–17092 (2011).

    Article  CAS  Google Scholar 

  6. Parsons, D.W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011).

    Article  CAS  Google Scholar 

  7. Berger, M.F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).

    Article  CAS  Google Scholar 

  8. Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).

    Article  CAS  Google Scholar 

  9. Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).

    Article  CAS  Google Scholar 

  10. Stephens, P.J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).

    Article  CAS  Google Scholar 

  11. Makridakis, N.M. & Reichardt, J.K. Translesion DNA polymerases and cancer. Front. Genet. 3, 174 (2012).

    Article  CAS  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Harris, R.S., Petersen-Mahrt, S.K. & Neuberger, M.S. RNA editing enzyme APOBEC1 and some of its homologs can act as DNA mutators. Mol. Cell 10, 1247–1253 (2002).

    Article  CAS  Google Scholar 

  15. Di Noia, J.M. & Neuberger, M.S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1–22 (2007).

    Article  CAS  Google Scholar 

  16. Longerich, S., Basu, U., Alt, F. & Storb, U. AID in somatic hypermutation and class switch recombination. Curr. Opin. Immunol. 18, 164–174 (2006).

    Article  CAS  Google Scholar 

  17. Conticello, S.G. The AID/APOBEC family of nucleic acid mutators. Genome Biol. 9, 229 (2008).

    Article  Google Scholar 

  18. LaRue, R.S. et al. Guidelines for naming nonprimate APOBEC3 genes and proteins. J. Virol. 83, 494–497 (2009).

    Article  CAS  Google Scholar 

  19. Malim, M.H. APOBEC proteins and intrinsic resistance to HIV-1 infection. Phil. Trans. R. Soc. Lond. B 364, 675–687 (2009).

    Article  CAS  Google Scholar 

  20. Harris, R.S., Hultquist, J.F. & Evans, D.T. The restriction factors of human immunodeficiency virus. J. Biol. Chem. 287, 40875–40883 (2012).

    Article  CAS  Google Scholar 

  21. Blanc, V. & Davidson, N.O. C-to-U RNA editing: mechanisms leading to genetic diversity. J. Biol. Chem. 278, 1395–1398 (2003).

    Article  CAS  Google Scholar 

  22. Bishop, K.N., Holmes, R.K., Sheehy, A.M. & Malim, M.H. APOBEC-mediated editing of viral RNA. Science 305, 645 (2004).

    Article  CAS  Google Scholar 

  23. Petit, V. et al. Murine APOBEC1 is a powerful mutator of retroviral and cellular RNA in vitro and in vivo. J. Mol. Biol. 385, 65–78 (2009).

    Article  CAS  Google Scholar 

  24. Ikeda, T. et al. Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons. Nucleic Acids Res. 39, 5538–5554 (2011).

    Article  CAS  Google Scholar 

  25. Petersen-Mahrt, S.K., Harris, R.S. & Neuberger, M.S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99–103 (2002).

    Article  CAS  Google Scholar 

  26. Petersen-Mahrt, S.K. & Neuberger, M.S. In vitro deamination of cytosine to uracil in single-stranded DNA by apolipoprotein B editing complex catalytic subunit 1 (APOBEC1). J. Biol. Chem. 278, 19583–19586 (2003).

    Article  CAS  Google Scholar 

  27. Pham, P., Bransteitter, R., Petruska, J. & Goodman, M.F. Processive AID-catalysed cytosine deamination on single-stranded DNA simulates somatic hypermutation. Nature 424, 103–107 (2003).

    Article  CAS  Google Scholar 

  28. Chelico, L., Pham, P., Calabrese, P. & Goodman, M.F. APOBEC3G DNA deaminase acts processively 3′ → 5′ on single-stranded DNA. Nat. Struct. Mol. Biol. 13, 392–399 (2006).

    Article  CAS  Google Scholar 

  29. Hultquist, J.F. et al. Human and rhesus APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H demonstrate a conserved capacity to restrict Vif-deficient HIV-1. J. Virol. 85, 11220–11234 (2011).

    Article  CAS  Google Scholar 

  30. Robbiani, D.F. & Nussenzweig, M.C. Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase. Annu. Rev. Pathol. 8, 79–103 (2013).

    Article  CAS  Google Scholar 

  31. Okazaki, I.M. et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173–1181 (2003).

    Article  CAS  Google Scholar 

  32. Yamanaka, S. et al. Apolipoprotein B mRNA-editing protein induces hepatocellular carcinoma and dysplasia in transgenic animals. Proc. Natl. Acad. Sci. USA 92, 8483–8487 (1995).

    Article  CAS  Google Scholar 

  33. Burns, M.B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366–370 (2013).

    Article  CAS  Google Scholar 

  34. Jarmuz, A. et al. An anthropoid-specific locus of orphan C to U RNA-editing enzymes on chromosome 22. Genomics 79, 285–296 (2002).

    Article  CAS  Google Scholar 

  35. 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).

    Article  CAS  Google Scholar 

  36. Koning, F.A. et al. Defining APOBEC3 expression patterns in human tissues and hematopoietic cell subsets. J. Virol. 83, 9474–9485 (2009).

    Article  CAS  Google Scholar 

  37. Lackey, L. et al. APOBEC3B and AID have similar nuclear import mechanisms. J. Mol. Biol. 419, 301–314 (2012).

    Article  CAS  Google Scholar 

  38. Kohli, R.M. et al. Local sequence targeting in the AID/APOBEC family differentially impacts retroviral restriction and antibody diversification. J. Biol. Chem. 285, 40956–40964 (2010).

    Article  CAS  Google Scholar 

  39. Wang, M., Rada, C. & Neuberger, M.S. Altering the spectrum of immunoglobulin V gene somatic hypermutation by modifying the active site of AID. J. Exp. Med. 207, 141–153 (2010).

    Article  CAS  Google Scholar 

  40. Albin, J.S. & Harris, R.S. Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: implications for therapeutics. Expert Rev. Mol. Med. 12, e4 (2010).

    Article  Google Scholar 

  41. Palles, C. et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45, 136–144 (2013).

    Article  CAS  Google Scholar 

  42. Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).

    Article  CAS  Google Scholar 

  43. Berger, M.F. et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485, 502–506 (2012).

    Article  CAS  Google Scholar 

  44. Fujino, T., Navaratnam, N. & Scott, J. Human apolipoprotein B RNA editing deaminase gene (APOBEC1). Genomics 47, 266–275 (1998).

    Article  CAS  Google Scholar 

  45. Muramatsu, M. et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem. 274, 18470–18476 (1999).

    Article  CAS  Google Scholar 

  46. Stenglein, M.D., Burns, M.B., Li, M., Lengyel, J. & Harris, R.S. APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nat. Struct. Mol. Biol. 17, 222–229 (2010).

    Article  CAS  Google Scholar 

  47. Sato, Y. et al. Deficiency in APOBEC2 leads to a shift in muscle fiber type, diminished body mass, and myopathy. J. Biol. Chem. 285, 7111–7118 (2010).

    Article  CAS  Google Scholar 

  48. Rogozin, I.B., Basu, M.K., Jordan, I.K., Pavlov, Y.I. & Koonin, E.V. APOBEC4, a new member of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases predicted by computational analysis. Cell Cycle 4, 1281–1285 (2005).

    Article  CAS  Google Scholar 

  49. Rada, C., Jarvis, J.M. & Milstein, C. AID-GFP chimeric protein increases hypermutation of Ig genes with no evidence of nuclear localization. Proc. Natl. Acad. Sci. USA 99, 7003–7008 (2002).

    Article  CAS  Google Scholar 

  50. Land, A.M. et al. Endogenous APOBEC3A DNA cytosine deaminase is cytoplasmic and non-genotoxic. J. Biol. Chem. 288, 17253–17260 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank The Cancer Genome Atlas (TCGA) Network for generating the RNA-seq and somatic mutation data and for providing open access, and we thank the Harris laboratory members and S. Kaufmann for comments. M.B.B. was supported by a Department of Defense Breast Cancer Research Program Predoctoral Fellowship (BC101124). This work was supported by grants from the Jimmy V Foundation, the Minnesota Ovarian Cancer Alliance and the US National Institutes of Health (R01 AI064046 and P01 GM091743).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA

    Michael B Burns, Nuri A Temiz & Reuben S Harris

  2. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA

    Michael B Burns, Nuri A Temiz & Reuben S Harris

  3. Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA

    Michael B Burns & Reuben S Harris

  4. Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, USA

    Michael B Burns & Reuben S Harris

Authors
  1. Michael B Burns
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nuri A Temiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reuben S Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study design, data analysis and manuscript preparation. M.B.B. and N.A.T. analyzed data from TCGA. N.A.T. performed mutation and cluster analysis.

Corresponding author

Correspondence to Reuben S Harris.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1–3 (PDF 1276 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burns, M., Temiz, N. & Harris, R. Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet 45, 977–983 (2013). https://doi.org/10.1038/ng.2701

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2701

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer