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

Document Type

Article

Publication Date

7-2-2026

Abstract

BACKGROUND: Tobacco use is linked to multiple cancer types and a quarter of cancer deaths. Tobacco smoke contains numerous mutagenic chemicals such as polycyclic aromatic hydrocarbons (PAH), however, the mutagenicity of many chemicals in tobacco products remains underexplored. The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), both International Agency for Research on Cancer (IARC) Group 1 carcinogens, form pre-mutagenic pyridyloxobutyl (POB) DNA adducts, yet little is known about the associated genomic mutation landscape(s) in humans. METHODS: We applied bulk and error-corrected next-generation sequencing to a battery of experimental systems comprising mammalian cell lines and animals exposed to NNK or NNN, and the extracted mutational signatures were compared to POB DNA adducts formed in the same models. A genome-scale POB mutational signature was extracted and characterized in detail and subsequently used for optimized per-sample signature attribution in ~ 6,670 cancer genomes from the International Cancer Genome Consortium Pan-Cancer Analysis of Whole Genomes (ICGC PCAWG) and The Cancer Genome Atlas (TCGA) collections. RESULTS: POB signatures generated in experimental exposure models share profiles dominated by T > N and C > T alterations, with transcription strand asymmetry indicative of damage on thymidines and cytidines. The T > N-dominated mutation profiles can be explained by O-POB-dT adducts, detected in the exposed cells. Stringent screening of 6,668 cancer genomes revealed the presence of a genome-scale POB signature in ~ 350 tumors from sites associated with tobacco smoking, that were distinct from cancer sites typically linked to known smoking-related single base substitution (SBS) signatures SBS4 and SBS92 linked to PAHs. These included hematological malignancies and cancers of the kidney, prostate, pancreas and breast, among other sites. In contrast and as expected, tobacco-smoking signatures SBS4 and SBS92 were jointly or individually predominant in cancers of the lung, liver, head-and-neck or bladder. CONCLUSIONS: Our study provides first-of-its-kind evidence for the presence of a tobacco-specific nitrosamine mutational signature in human tumors. It suggests that the POB pathway may contribute selectively to the mutational landscapes of certain cancers distinct from those affected by PAH compounds, indicating the potential roles of specific tobacco smoke chemicals in tobacco-linked cancer types lacking SBS4 or SBS92.

Publication Title

Genome medicine

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