Mechanisms Responsible for the Chromosome and Gene Mutations Driving Carcinogenesis: Implications for Dose-Response Characteristics of Mutagenic Carcinogens

Abstract

Through the use of ultra high throughput DNA sequencing techniques, it has been possible to characterize a number of tumour types at the molecular level. This has led to the concept that there are 'driver’ and ‘passenger’ mutations, with an estimate of the number of driver mutations being about 120 for all tumours characterized to date. Furthermore, it is proposed that for any particular tumour a subset of these driver mutations results in the development of the phenotypes underlying the six acquired characteristics defined by Hanahan and Weinberg in their Hallmarks of Cancer. In the framework of risk assessment, these acquired characteristics are key events along the pathway from a normal cell to a metastatic tumour that can be induced by DNA-reactive carcinogens. The nature of the dose–response curve for the driver mutations is influenced by the mechanism of induction of these mutations. In general, mutations (both gene and chromosomal) induced by DNA-reactive carcinogens are formed by replication errors on a damaged DNA template (i.e. DNA adducts). By considering such chemically induced mutations in the context of classical ‘hit’ theory, one hit is required to produce a gene mutation and two independent hits are required to produce a chromosomal mutation. The consequence is that the dose–response curve for gene mutations is linear and that for chromosome mutations is proportional to the square of the dose. Thus, for a typical DNA-reactive carcinogen that induces both gene and chromosomal mutations, the dose–response curve for total mutations will be a linear–quadratic with the form being influenced by the relative proportions of gene and chromosome mutations.