Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures

Recently we have investigated whether similar RNA/RT-based mutator mechanisms explain how de novo mutations arise in somatic tissues (cancer genomes). The data analyses indeed suggest that cancers arise via dysregulated “Ig-like SHM responses” involving rogue DNA and RNA deaminations coupled to genome-wide RT events. Further, Robyn Lindley has recently shown that the strand-biased mutations in cancer genome genes are also in “codon-context.” This has been termed Targeted Somatic Mutation (TSM) to highlight that mutations are far more targeted than previously thought in somatic tissues associated with disease. The TSM process implies an “in-frame DNA reader” whereby DNA and RNA deaminases at transcribed regions are guided in their mutagenic action, by the codon reading frame of the DNA.