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

In a new study, researchers from the International Agency for Research on Cancer (IARC) and partner institutions provide first-of-its-kind evidence for the presence of a tobacco-specific nitrosamine mutational signature in human tumours. This signature may contribute to the mutational landscape during the development of certain cancer types linked to tobacco use but mostly distinct from cancer sites linked to more well understood signatures of the polycyclic aromatic hydrocarbon (PAH) compounds found in tobacco smoke. The study was published the journal Genome Medicine.

The researchers sequenced systems comprising mammalian cell lines and animals exposed to the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or N′-nitrosonornicotine (NNN). They then related the resulting mutational signatures to pre-mutagenic pyridyloxobutyl (POB) DNA adducts formed in the same models, determining the chemical basis for the formation of a genome-scale POB mutational signature induced by either NNK or NNN. The scientists then mathematically screened about 7000 genomes of tumour samples with the POB signature and found it to be present in about 350 genomes from tumour sites associated with tobacco smoking. Importantly, the POB signature was found in separate cancer sites from those typically linked to known smoking-related single base substitution (SBS) signatures linked to PAHs (SBS4 and SBS92).

The sites exhibiting the POB signature included haematological malignancies and cancers of the kidney, prostate, pancreas, and breast, among other sites. In contrast and as expected, the tobacco-smoking signatures SBS4 and SBS92 were jointly or individually predominant in cancers of the lung, liver, head and neck, or bladder. The selective detection of the new POB signature in a distinct set of cancer types raises important questions about the potential roles of certain tobacco-smoke chemicals in tobacco-linked cancer types lacking SBS4 and SBS92, the fingerprints of PAH chemicals.

Korenjak M, Temiz NA, Keita S, Chavanel B, Renard C, Sirand C, et al.
Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK
Genome Med. Published online 2 July 2026;
https://doi.org/10.1186/s13073-026-01685-z

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