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.
Highlights
The sequencing of genomes of solid tumors and liquid malignancies associated with different types and stages of cancer has revealed a plethora of genetic changes, from nucleotide substitutions and insertions/deletions to chromosomal rearrangements and chromosome copy number alterations [1,2,3].As predicted decades ago by the mutator theory of cancer [4], the elevated mutability in tumors contributes both to their onset and to their further evolution
The information content of activation induced deaminase (AID)/APOBEC mutable motifs is shown in Figure 1
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 the somatic mutation spectra attributed to APOBECs in cancer genomes
Summary
The sequencing of genomes of solid tumors and liquid malignancies associated with different types and stages of cancer has revealed a plethora of genetic changes, from nucleotide substitutions and insertions/deletions to chromosomal rearrangements and chromosome copy number alterations [1,2,3].As predicted decades ago by the mutator theory of cancer [4], the elevated mutability in tumors contributes both to their onset and to their further evolution. The sequencing of genomes of solid tumors and liquid malignancies associated with different types and stages of cancer has revealed a plethora of genetic changes, from nucleotide substitutions and insertions/deletions to chromosomal rearrangements and chromosome copy number alterations [1,2,3]. A few driver mutations [6,7] lead to cancer, while the role, if any, of the vast majority of mutations, termed “passengers”, during tumor development is poorly understood [8,9]. Different mutagenic processes generate mutations within different contexts of a neighboring nucleotide sequence (the bases upstream and/or downstream of the mutations, termed “mutation signatures”). Sophisticated approaches have been developed to extract the most prominent signatures from a complex mix of mutational targets resulting from the action of a variety of mutagens, both exogenous and endogenous, operating during tumor evolution [12,13]
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