The Complexity of Tobacco Smoke-Induced Mutagenesis in Head and Neck Cancer

Abstract

Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). Here, we further explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and three additional alcohol-related signatures indicating synergism between the two exposures. Tobacco smoking was associated with differences in the mutational spectra and repertoire of driver mutations in cancer genes, and in patterns of copy number change. Together, the results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones.

Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK

“…Multiple tobacco smoke chemicals likely contribute to the main features of SBS4, for which benzo[a]pyrene (BaP) and other polycyclic aromatic hydrocarbons (PAH) have been cited as likely causes of mutations at guanine residues [32][33][34][35] while SBS4 also contains T>A transversions, with the underlying adenine damage previously linked to the effects of other PAH or to glycidamide, a genotoxic metabolite of the tobacco-smoke chemical acrylamide 32,35 . Recently, additional mutational signatures of yet unknown etiologies with predominant T>A alterations have been linked to tobacco smoking 36,37 . SBS4 further associates with signature ID3, characterized by single base deletions of predominantly C, with signature DBS2, characterized predominantly by CC>AA doublets, and with DBS6, harboring mostly TG>AT and TG>CT. SBS29 is similar to but discernible from SBS4, possibly as PAHs like BaP are less abundant in smokeless tobacco.…”