%0 Journal Article
%T Critical Analysis of Strand-Biased Somatic Mutation Signatures in TP53 versus Ig Genes, in Genome-Wide Data and the Etiology of Cancer
%A Robyn A. Lindley
%A Edward J. Steele
%J ISRN Genomics
%D 2013
%R 10.1155/2013/921418
%X 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¡ªand in genome-wide data¡ªthat 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
%U http://www.hindawi.com/journals/isrn.genomics/2013/921418/