Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK
11 affiliations
- 1International Agency for Research on Cancer, Lyon, France
- 2University of Minnesota
- 3Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
- 4Department of Civil, Environmental, and Geospatial Engineering, Michigan Technological University, Houghton, MI, United States
- 5Servier Pharmaceuticals, Boston, MA, United States
- 6USAMV Cluj-Napoca
- 7Department of Pathology, Faculty of Veterinary Medicine, Ankara University, Ankara, Turkey
- 8Altos Labs, Los Altos, CA, United States
- 9Moores Cancer Center, University of California San Diego, La Jolla, CA, United States
- 10University Claude Bernard Lyon 1, INSERM U1052 CNRS UMR5286, Cancer Research Center, Centre Leon Berard, Lyon, France
- 11University Claude Bernard Lyon 1, INSERM U52 CNRS UMR5286, Cancer Research Center, Centre Leon Berard, Lyon, France
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-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.
Related
- Mutational signature landscape of pancreatic cancer genomes from nine countries
- Deep Learning-Based Inference of Mutational Signature Exposures from Histology Across Tumour Types
- Production of abundant defective viral genomes by an insect-specific alphavirus revealed by nanopore sequencing
- Elucidating the Gene Expression Signature of Rosai–Dorfman Disease: A Study from the Atlas of Blood Cancer Genomes Initiative
- Fusion-specific co-mutational architecture and treatment-response associations in pediatric core-binding factor acute myeloid leukemia: a multicenter exome-profiled cohort
BibTeX
@article{korenjak2026human,
title = {{Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK}},
author = {Michael Korenjak and Nuri A. Temiz and Stéphane Keïta and Bérénice Chavanel and Claire Renard and Cécilia Sirand and Vincent Cahais and Tanguy Mayel and Karin R. Vevang and Foster C. Jacobs and Jiehong Guo and William E. Smith and Marissa K. Oram and Flaviu Tăbăran and Ozan Ahlat and Ingrid Cornax and M. Gerard O’Sullivan and Samrat Das and Shuvro Prokash Nandi and Yuhe Cheng and Ludmil B. Alexandrov and Silvia Balbo and Stephen S. Hecht and Sergey Senkin and François Virard and Lisa A. Peterson and Jiří Zavadil},
journal = {Genome Medicine},
year = {2026},
month = jul,
doi = {10.1186/s13073-026-01685-z},
url = {https://doi.org/10.1186/s13073-026-01685-z},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK
AU - Michael Korenjak
AU - Nuri A. Temiz
AU - Stéphane Keïta
AU - Bérénice Chavanel
AU - Claire Renard
AU - Cécilia Sirand
AU - Vincent Cahais
AU - Tanguy Mayel
AU - Karin R. Vevang
AU - Foster C. Jacobs
AU - Jiehong Guo
AU - William E. Smith
AU - Marissa K. Oram
AU - Flaviu Tăbăran
AU - Ozan Ahlat
AU - Ingrid Cornax
AU - M. Gerard O’Sullivan
AU - Samrat Das
AU - Shuvro Prokash Nandi
AU - Yuhe Cheng
AU - Ludmil B. Alexandrov
AU - Silvia Balbo
AU - Stephen S. Hecht
AU - Sergey Senkin
AU - François Virard
AU - Lisa A. Peterson
AU - Jiří Zavadil
PY - 2026
DA - 2026/07/02
JO - Genome Medicine
DO - 10.1186/s13073-026-01685-z
UR - https://doi.org/10.1186/s13073-026-01685-z
AB - 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-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.
SN - 1756-994X
ER -