Critical Analysis of Strand-Biased Somatic Mutation Signatures in TP53versusIg Genes, in Genome-Wide Data and the Etiology of Cancer

Robyn A Lindley,Edward J Steele

doi:10.1155/2013/921418

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 totoor 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.

Highlights

All of these can be considered as “directly accessible to tobacco smoke carcinogens.” is choice is made despite the known complexity of breast cancer in both etiology and the diversity of histological subtypes [1] as a similar pattern is evident in mutated TP53 variants in “All Bladder Cancers” which are likely to be more directly exposed to tobacco smoke-derived carcinogenic metabolites in urine
Our analysis shows that the underlying “endogenous” strand-biased mutation signatures in TP53, for many different non-lymphoid cancers, bear a striking resemblance to the Ig somatic hypermutation (SHM) pattern. is allows inferences to be drawn about the mechanistic role of TP53-mediated DNA repair
What we discovered in a preliminary analysis was that the characteristic strandbiased mutation signatures of Ig SHM were present, in toto or in part, in a number of somatic mutation datasets posted at the Welcome Trust Sanger Institute’s website run by the institute’s Cancer Genome Project [4]

Summary

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 (A atoxin B1, G-to-T; Aristolochic acid, Ato-T), or UV radiation in sun exposure causing DNA photoproducts such as cyclobutane pyrimidine dimers, C-to-T reviewed in Soussi [1]. e 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]. ere is 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. Ere is 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 This basic “endogenous” pattern is evident in many tumors outside of lung, head, neck, and oesophagus. ISRN Genomics regulation and base-modi ed RNA template intermediates coupled to reverse transcription in the genesis of many cancers It is consistent with the view that the normally tightly regulated mutation processes targeting VDJ genes in B lymphocytes may, following further loss of DNA damage response regulation by TP53, be inappropriately turned on in non-lymphoid tissues, for example, by hormonal and/or in ammation-related processes, leading to cancer

Background

Findings

C AC mRNA TS