The pathogenesis of increased cancer risk due to tobacco smoking

STRATTON M. ²

Tobacco smoking is a recognised cause of multiple cancer types including lung, oral cavity, pharynx-larynx, esophagus, bladder, cervix, liver, kidney, stomach, pancreas, colorectum and bone marrow (AML). More than 60 chemicals in tobacco smoke are carcinogenic. A major mechanistic hypothesis underlying tobacco-smoke induced carcinogenesis is that some of these chemicals damage DNA in somatic cells resulting in an increased somatic mutation burden which increases the chance of a cell converting into a neoplastic clone. To investigate this hypothesis, we analysed 12 cancer types with elevated risks due to tobacco smoking. Our examination included single base mutations, small insertions and deletions, copy number variations, chromosomal rearrangements, and methylation profiles derived from the cancer genomes of 2,231 smokers and 1,023 lifelong non-smokers. Lung adenocarcinoma and larynx-pharynx cancer, both arising from tissues directly exposed to tobacco smoke, show markedly increased mutation burdens in smokers compared to non-smokers of a mutational signature that arises as a result of DNA damage caused by tobacco smoke mutagens. However, other cancer types caused by tobacco smoking, many arising in tissues not directly exposed to tobacco smoke, do not show evidence of this signature. Across all cancer types, other mutational signatures are influenced by smoking. In some cancer types, there was no elevation in somatic mutations or changes in methylation profiles between smokers and non-smokers. The results indicate that the pathogenesis of tobacco smoking induced elevated cancer risk is complex, differs between cancer types and in some cancer types is enigmatic.