Critical Analysis of Strand-Biased Somatic Mutation Signatures in TP53 versus Ig Genes, in Genome-Wide Data and the Etiology of Cancer

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 non-lymphoid 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. 1. Introduction A major goal of this paper is to provide an explanation of the origin of the main strand-biased mutation signatures observed in the TP53 tumor suppressor gene in the many tumors likely to arise by “endogenous” mutation processes: that is to say, those cancers not caused by well-known exogenous mechanisms such as exposure to carcinogens in tobacco smoke (Benzo(a)pyrene, G-to-T), toxins in food contamination (Aflatoxin B1, G-to-T; Aristolochic acid, A-to-T), or UV radiation in sun exposure causing DNA photoproducts such as cyclobutane pyrimidine dimers, C-to-T reviewed in Soussi [1]. The TP53 mutation pattern in “All Breast Cancers” has been chosen as representative of the TP53 “endogenous pattern” as this mutation pattern appears to arise in a tissue “least accessible to carcinogens in tobacco smoke” or directly exposed to such exogenous carcinogens; see Hainaut and Pfeifer [2]. There is also a large number of TP53 point mutations in this tissue category (>1000), similar to the numbers in “All Lung Cancers,” the major comparator in the analysis. Further, this basic “endogenous” pattern is evident in many tumors outside of lung, head, neck, and oesophagus. All of these can be considered as