Nucleotide weight matrices reveal ubiquitous mutational footprints of AID/APOBEC deaminases in human cancer genomes

Igor B. Rogozin, Abiel Roche-Lima, Artem G. Lada, Frida Belinky, Ivan A. Sidorenko, Galina V. Glazko, Vladimir N. Babenko, David N. Cooper, Youri I. Pavlov

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Cancer genomes accumulate nucleotide sequence variations that number in the tens of thousands per genome. A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases. These enzymes, collectively called activation induced deaminase (AID)/APOBECs, deaminate cytosines located within defined DNA sequence contexts. The resulting changes of the original C:G pair in these contexts (mutational signatures) provide indirect evidence for the participation of specific cytosine deaminases in a given cancer type. The conventional method used for the analysis of mutable motifs is the consensus approach. Here, for the first time, we have adopted the frequently used weight matrix (sequence profile) approach for the analysis of mutagenesis and provide evidence for this method being a more precise descriptor of mutations than the sequence consensus approach. We confirm that while mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the action of the humoral immune response somatic hypermutation enzyme, AID, are the most widespread feature of somatic mutation spectra attributable to deaminases in cancer genomes. Overall, the weight matrix approach reveals that somatic mutations are significantly associated with at least one AID/APOBEC mutable motif in all studied cancers.

Original languageEnglish (US)
Article number211
JournalCancers
Volume11
Issue number2
DOIs
StatePublished - Feb 2019

Keywords

  • AID/APOBEC
  • Activation induced deaminase
  • DNA sequence profile
  • Mixture of normal distributions
  • Monte Carlo
  • Mutable motif
  • Somatic mutation
  • Tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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