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RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer

Damian Wojtowicz, Jan Hoinka, Bayarbaatar Amgalan, Yoo-Ah Kim, Teresa M. Przytycka
doi: https://doi.org/10.1101/2020.11.21.392878
Damian Wojtowicz
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
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  • For correspondence: wojtowda@ncbi.nlm.nih.gov przytyck@ncbi.nlm.nih.gov
Jan Hoinka
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
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Bayarbaatar Amgalan
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
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Yoo-Ah Kim
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
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Teresa M. Przytycka
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health
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  • For correspondence: wojtowda@ncbi.nlm.nih.gov przytyck@ncbi.nlm.nih.gov
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Abstract

Many mutagenic processes leave characteristic imprints on cancer genomes known as mutational signatures. These signatures have been of recent interest regarding their applicability in studying processes shaping the mutational landscape of cancer. In particular, pinpointing the presence of altered DNA repair pathways can have important therapeutic implications. However, mutational signatures of DNA repair deficiencies are often hard to infer. This challenge emerges as a result of deficient DNA repair processes acting by modifying the outcome of other mutagens. Thus, they exhibit non-additive effects that are not depicted by the current paradigm for modeling mutational processes as independent signatures. To close this gap, we present RepairSig, a method that accounts for interactions between DNA damage and repair and is able to uncover unbiased signatures of deficient DNA repair processes. In particular, RepairSig was able to replace three MMR deficiency signatures previously proposed to be active in breast cancer, with just one signature strikingly similar to the experimentally derived signature. As the first method to model interactions between mutagenic processes, RepairSig is an important step towards biologically more realistic modeling of mutational processes in cancer. The source code for RepairSig is publicly available at https://github.com/ncbi/RepairSig.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* First authors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Posted November 22, 2020.
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RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer
Damian Wojtowicz, Jan Hoinka, Bayarbaatar Amgalan, Yoo-Ah Kim, Teresa M. Przytycka
bioRxiv 2020.11.21.392878; doi: https://doi.org/10.1101/2020.11.21.392878
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RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer
Damian Wojtowicz, Jan Hoinka, Bayarbaatar Amgalan, Yoo-Ah Kim, Teresa M. Przytycka
bioRxiv 2020.11.21.392878; doi: https://doi.org/10.1101/2020.11.21.392878

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