Critical analysis of strand-biased somatic mutation signatures in TP53 versus Ig genes, in genome-wide data and the etiology of cancer

Lindley, R.A. and Steele, E.J. (2012) Critical analysis of strand-biased somatic mutation signatures in TP53 versus Ig genes, in genome-wide data and the etiology of cancer. ISRN Genomics, In Press .

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Abstract

Previous analyses of rearranged immunoglobulin (Ig) variable genes (VDJs) concluded that the mechanism of Ig somatic hypermutation (SHM) involves the Ig pre-mRNA acting as a copying template resulting in characteristic strand-biased somatic mutation patterns at A:T and G:C base pairs. We have since analysed cancer genome data and found the same mutation strand-biases, in toto or in part, in nonlymphoid cancers. Here we have analysed somatic mutations in a single well characterised gene TP53. Our goal is to understand the genesis of the strand-biased mutation patterns in TP53 - and in genome-wide data - that may arise by "endogenous" mechanisms as opposed to adduct-generated DNA-targeted strand-biased mutations caused by well characterised "external" carcinogenic influences in cigarette smoke, UV-light and certain dietary components. The underlying strand-biased mutation signatures in TP53, for many nonlymphoid cancers, bear a striking resemblance to the Ig SHM pattern. A similar pattern can be found in genome-wide somatic mutations in cancer genomes that have also mutated TP53. The analysis implies a role for base-modified RNA template intermediates coupled to reverse transcription in the genesis of many cancers. Thus Ig SHM may be inappropriately activated in many non-lymphoid tissues via hormonal and/or inflammation-related processes leading to cancer.