Abstract
Reporter gene assays, in which a single mutation from each experiment can contribute to the assembly of a mutation spectrum for an agent, have provided the basis for understanding the mutational processes induced by mutagenic agents and for providing clues to the origins of mutations in human tumours. More recently exome and whole genome sequencing of human tumours has revealed distinct patterns of mutation that could provide additional clues for the causative origins of cancer. This can be tested by examining the mutational signatures induced in experimental systems by putative cancer-causing agents. Such signatures are now being generated in vitro in a number of different mutagen-exposed cellular systems. Results reveal that mutagens induce characteristic mutation signatures that, in some cases, match signatures found in human tumours. Proof of principle has been established with mutational signatures generated by simulated sunlight and aristolochic acid, which match those signatures found in human melanomas and urothelial cancers, respectively. In an analysis of somatic mutations in cancers for which tobacco smoking confers an elevated risk, it was found that smoking is associated with increased mutation burdens of multiple different mutational signatures, which contribute to different extents in different tissues. One of these signatures, mainly found in tissues directly exposed to tobacco smoke, is attributable to misreplication of DNA damage caused by tobacco carcinogens. Others likely reflect indirect activation of DNA editing by APOBEC cytidine deaminases and of an endogenous clock-like mutational process. The results are consistent with the proposition that smoking increases cancer risk by increasing the somatic mutation load although direct evidence for this mechanism is lacking in some cancer types. Thus, next generation sequencing of exomes or whole genomes is providing new insights into processes underlying the causes of human cancer.
Highlights
Cancers arise as a result of somatic mutations
Reporter gene assays, in which a single mutation from each experiment can contribute to the assembly of a mutation spectrum for an agent, have provided the basis for understanding the mutational processes induced by mutagenic agents and for providing clues to the origins of mutations in human tumours
In order to examine systematically the mutational patterns associated with treatment of a comprehensive selection of environmental mutagens generated under highly controlled conditions, 79 chemicals/agents were selected on the basis that they are environmental or therapeutic agents that have been classified by the International Agency for Research on Cancer (IARC) as human carcinogens (Group 1), probable human carcinogens (Group 2A) or possible human carcinogens (Group 2B) [31]
Summary
Cancers arise as a result of somatic mutations. All tumours have been found to contain multiple mutations, including point mutations, insertions, deletions and gene rearrangements. Mutations that occur in critical genes involved in processes that maintain the integrity of cells (the ‘driver’ mutations) and that when mutated confer a growth advantage, can be considered causative in transforming a normal cell into a malignant one. Many other mutations are present in tumours (the ‘passenger’ mutations), accumulated as a result of genomic instability induced by the transformed or malignant state, or as bystander mutations arising from the same influences that gave rise to the ‘driver’ mutations, but occurring in regions of the genome that do not cause the phenotypic changes causing the emergence of the transformed state. A cancer genome can be considered to contain the history of mutagenic processes that have occurred throughout the life of the cancer patient, both before and after the acquisition of a neoplastic transformation phenotype by the progenitor cell of the tumour
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