Letter | Published:

An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers

Nature Genetics volume 47, pages 10671072 (2015) | Download Citation

Abstract

Elucidation of mutagenic processes shaping cancer genomes is a fundamental problem whose solution promises insights into new treatment, diagnostic and prevention strategies1. Single-strand DNA–specific APOBEC cytidine deaminase(s) are major source(s) of mutation in several cancer types2,3,4. Previous indirect evidence implicated APOBEC3B as the more likely major mutator deaminase, whereas the role of APOBEC3A is not established5,6. Using yeast models enabling the controlled generation of long single-strand genomic DNA substrates7, we show that the mutation signatures of APOBEC3A and APOBEC3B are statistically distinguishable. We then apply three complementary approaches to identify cancer samples with mutation signatures resembling either APOBEC. Strikingly, APOBEC3A-like samples have over tenfold more APOBEC-signature mutations than APOBEC3B-like samples. We propose that APOBEC3A-mediated mutagenesis is much more frequent because APOBEC3A itself is highly proficient at generating DNA breaks8,9,10, whose repair can trigger the formation of single-strand hypermutation substrates.

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Acknowledgements

We thank T.A. Kunkel, S.A. Lujan and D.V. Zaykin for critical reading of the manuscript. This work was supported by US National Institutes of Health Intramural Research Program Project Z1AES103266 to D.A.G. and US National Institutes of Health grants U24CA143845 to G.G., R01GM052319 to P.A.M., 1P01CA120964 to D.J.K., R00ES022633 to S.A.R. and K99ES024424 to K.C.

Author information

Affiliations

  1. Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.

    • Kin Chan
    • , Steven A Roberts
    • , Joan F Sterling
    • , Natalie Saini
    •  & Dmitry A Gordenin
  2. School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.

    • Steven A Roberts
  3. Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, North Carolina, USA.

    • Leszek J Klimczak
    •  & David C Fargo
  4. Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Ewa P Malc
    •  & Piotr A Mieczkowski
  5. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Jaegil Kim
    • , David J Kwiatkowski
    •  & Gad Getz
  6. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • David J Kwiatkowski
  7. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Gad Getz

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Contributions

K.C. and D.A.G. designed the study. K.C., S.A.R., J.F.S., N.S., E.P.M. and P.A.M. performed the experiments. K.C., L.J.K., J.K., D.C.F. and G.G. performed statistical analyses. K.C., L.J.K., N.S., J.K., D.J.K., D.C.F., G.G. and D.A.G. analyzed the data. S.A.R., L.J.K. and P.A.M. contributed reagents, materials or analysis tools. K.C. and D.A.G. wrote the manuscript, with contributions from S.A.R., N.S., D.J.K. and G.G.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dmitry A Gordenin.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6.

Excel files

  1. 1.

    Supplementary Table 1

    This file summarizes the yeast data obtained in this study, as well as reanalysis of data previously published in Taylor et al., 2013 (ref.31).

  2. 2.

    Supplementary Table 2

    This file contains data used for computing enrichment values from each cancer data set.

  3. 3.

    Supplementary Table 3

    This file summarizes data pertaining to minimal estimates of TCA→TGA/TTA mutations added by APOBEC(s) in six whole-genome cohorts.

  4. 4.

    Supplementary Table 4

    This file contains the sequences of the primers used to amplify each A3A/A3B-hph cassette by PCR for targeted gene replacement of LEU2 in yeast.

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DOI

https://doi.org/10.1038/ng.3378

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