Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). We explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC samples 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 alcohol-related signatures, indicating a combined effect of these exposures. Tobacco smoking was associated with differences in the mutational spectra, repertoire of driver mutations in cancer genes and patterns of copy number change. Our results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones.

A C Camargo Cancer Center São Paulo Brazil

Associação de Combate ao Câncer em Goiás Hospital Araújo Jorge Goiânia Brazil

Barretos Cancer Hospital Barretos Brazil

Bioinformatics and Systems Biology Graduate Program University of California San Diego La Jolla CA USA

Biomedical Sciences Graduate Program University of California San Diego La Jolla CA USA

Brazilian National Cancer Institute Rio de Janeiro Brazil

Cancer Ageing and Somatic Mutation Wellcome Sanger Institute Cambridge UK

Cancer Epidemiology Unit The Nuffield Department of Population Health University of Oxford Oxford UK

Carol Davila University of Medicine and Pharmacy Bucharest Romania

Charles University Prague 2nd Faculty of Medicine IPHPM Prague Czech Republic

Department of Bioengineering University of California San Diego La Jolla CA USA

Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA

Evidence Synthesis and Classification Branch International Agency for Research on Cancer Lyon France

Genomic Epidemiology Branch International Agency for Research on Cancer Lyon France

Hospital Santa Rita de Cássia Associação Feminina de Educação e Combate ao Câncer Vitória Brazil

Hospital Universitario Fundación Santa Fe de Bogotá Bogotá Colombia

Instituto de Oncología 'Angel Roffo' Universidad de Buenos Aires Buenos Aires Argentina

Moores Cancer Center University of California San Diego La Jolla CA USA

National Institute of Public Health Bucharest Romania

Pathology Department Federal University of Espírito Santo Vitória Brazil

Regional Authority of Public Health Banská Bystrica Slovak Republic

Saint Mary Clinic of General and Esophageal Surgery Bucharest Romania

Sanford Stem Cell Institute University of California San Diego La Jolla CA USA

School of Medicine National and Kapodistrian University of Athens Athens Greece

Unit of Biostatistics Epidemiology and Public Health Department of Cardio Thoraco Vascular Sciences and Public Health University of Padua Padova Italy

Unit of Cancer Epidemiology Centro di Riferimento Oncologico di Aviano IRCCS Aviano Italy

University of São Paulo Medical School São Paulo Brazil

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medRxiv. 2024 Apr 17:2024.04.15.24305006. doi: 10.1101/2024.04.15.24305006. PubMed

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Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. PubMed DOI

Simard, E. P., Torre, L. A. & Jemal, A. International trends in head and neck cancer incidence rates: differences by country, sex and anatomic site. PubMed DOI

IARC. PubMed PMC

IARC. PubMed PMC

IARC. PubMed PMC

Hashim, D. et al. The role of oral hygiene in head and neck cancer: results from International Head and Neck Cancer Epidemiology (INHANCE) consortium. PubMed DOI PMC

Gaudet, M. M. et al. Body mass index and risk of head and neck cancer in a pooled analysis of case–control studies in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. PubMed DOI PMC

Loomis, D. et al. Carcinogenicity of drinking coffee, mate, and very hot beverages. PubMed DOI

Hashibe, M. et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. PubMed DOI PMC

Lubin, J. H. et al. Total exposure and exposure rate effects for alcohol and smoking and risk of head and neck cancer: a pooled analysis of case–control studies. PubMed DOI PMC

Perdomo, S. et al. The Mutographs biorepository: a unique genomic resource to study cancer around the world. PubMed DOI PMC

Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. PubMed DOI PMC

Moody, S. et al. Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence. PubMed DOI

Alexandrov, L. B. et al. Mutational signatures associated with tobacco smoking in human cancer. PubMed DOI PMC

Islam, S. M. A. et al. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor. PubMed DOI PMC

Letouzé, E. et al. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. PubMed DOI PMC

Plath, M. et al. Unraveling most abundant mutational signatures in head and neck cancer. PubMed DOI

Gillison, M. L. et al. Human papillomavirus and the landscape of secondary genetic alterations in oral cancers. PubMed DOI PMC

Yang, J., Chen, Y., Luo, H. & Cai, H. The landscape of somatic copy number alterations in head and neck squamous cell carcinoma. PubMed PMC

Sayáns, M. P. et al. Comprehensive genomic review of TCGA head and neck squamous cell carcinomas (HNSCC). PubMed DOI PMC

Slot, D. E., Van Der Weijden, F. & Ciancio, S. G. Oral health, dental care and mouthwash associated with upper aerodigestive tract cancer risk in Europe: the ARCAGE study. PubMed DOI

Gerstung, M. et al. The evolutionary history of 2,658 cancers. PubMed DOI PMC

Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. PubMed DOI PMC

Leemans, C. R., Snijders, P. J. F. & Brakenhoff, R. H. The molecular landscape of head and neck cancer. PubMed DOI

Steele, C. D. et al. Signatures of copy number alterations in human cancer. PubMed DOI PMC

Meyer, N. & Penn, L. Z. Reflecting on 25 years with MYC. PubMed DOI

Steele, C. D., Pillay, N. & Alexandrov, L. B. An overview of mutational and copy number signatures in human cancer. PubMed DOI PMC

Cogliano, V. J. et al. Preventable exposures associated with human cancers. PubMed DOI PMC

Hecht, S. S. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. PubMed DOI

Nik-Zainal, S. et al. The genome as a record of environmental exposure. PubMed PMC

Kucab, J. E. et al. A compendium of mutational signatures of environmental agents. PubMed DOI PMC

Westcott, P. M. K. et al. The mutational landscapes of genetic and chemical models of Kras-driven lung cancer. PubMed DOI PMC

Pfeifer, G. P. et al. Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. PubMed DOI

Hecht, S. S. & Hatsukami, D. K. Smokeless tobacco and cigarette smoking: chemical mechanisms and cancer prevention. PubMed DOI PMC

Peterson, L. A. Context matters: contribution of specific DNA adducts to the genotoxic properties of the tobacco-specific nitrosamine NNK. PubMed DOI PMC

Mingard, C. et al. Dissection of cancer mutational signatures with individual components of cigarette smoking. PubMed DOI PMC

Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. PubMed DOI PMC

Deneuve, S. et al. Molecular landscapes of oral cancers of unknown etiology. Preprint at

Degawa, M. et al. Metabolic activation and carcinogen–DNA adduct detection in human larynx. PubMed

Jones, N. J., McGregor, A. D. & Waters, R. Detection of DNA adducts in human oral tissue: correlation of adduct levels with tobacco smoking and differential enhancement of adducts using the butanol extraction and nuclease P1 versions of 32P postlabeling. PubMed

Yamazaki, H., Inui, Y., Yun, C. H., Guengerich, F. P. & Shimada, T. Cytochrome P450 2E1 and 2A6 enzymes as major catalysts for metabolic activation of N-nitrosodialkylamines and tobacco-related nitrosamines in human liver microsomes. PubMed DOI

Hoes, L., Dok, R., Verstrepen, K. J. & Nuyts, S. Ethanol-induced cell damage can result in the development of oral tumors. PubMed DOI PMC

Gapstur, S. M. et al. The IARC perspective on alcohol reduction or cessation and cancer risk. PubMed DOI

Pickering, C. R. et al. Squamous cell carcinoma of the oral tongue in young non-smokers is genomically similar to tumors in older smokers. PubMed DOI PMC

Lawrence, M. S. et al. Comprehensive genomic characterization of head and neck squamous cell carcinomas. PubMed DOI PMC

Riva, L. et al. The mutational signature profile of known and suspected human carcinogens in mice. PubMed DOI PMC

IARC. PubMed PMC

Agrawal, A. et al. UV radiation increases carcinogenic risks for oral tissues compared to skin. PubMed DOI

Von Koschembahr, A. et al. Solar simulated light exposure alters metabolization and genotoxicity induced by benzo[a]pyrene in human skin. PubMed DOI PMC

King, G. N. et al. Increased prevalence of dysplastic and malignant lip lesions in renal-transplant recipients. PubMed DOI

Sugano, N., Minegishi, T., Kawamoto, K. & Ito, K. Nicotine inhibits UV-induced activation of the apoptotic pathway. PubMed DOI

Onoda, N. et al. Nicotine affects the signaling of the death pathway, reducing the response of head and neck cancer cell lines to DNA damaging agents. PubMed DOI

Reid, T. M. & Loeb, L. A. Tandem double CC–>TT mutations are produced by reactive oxygen species. PubMed DOI PMC

Javadzadeh, S. et al. FastViFi: fast and accurate detection of (hybrid) viral DNA and RNA. PubMed DOI PMC

Wang, Q., Jia, P. & Zhao, Z. VERSE: a novel approach to detect virus integration in host genomes through reference genome customization. PubMed DOI PMC

Whalley, J. P. et al. Framework for quality assessment of whole genome cancer sequences. PubMed DOI PMC

Bergmann, E. A., Chen, B. J., Arora, K., Vacic, V. & Zody, M. C. Conpair: concordance and contamination estimator for matched tumor–normal pairs. PubMed DOI PMC

Van Loo, P. et al. Allele-specific copy number analysis of tumors. PubMed DOI PMC

Nik-Zainal, S. et al. The life history of 21 breast cancers. PubMed DOI PMC

Jones, D. et al. cgpCaVEManWrapper: simple execution of CaVEMan in order to detect somatic single nucleotide variants in NGS data. PubMed DOI PMC

Raine, K. M. et al. cgpPindel: identifying somatically acquired insertion and deletion events from paired end sequencing. PubMed DOI PMC

Kim, S. et al. Strelka2: fast and accurate calling of germline and somatic variants. PubMed DOI

Bergstrom, E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. PubMed DOI PMC

Liu, M., Wu, Y., Jiang, N., Boot, A. & Rozen, S. G. mSigHdp: hierarchical Dirichlet process mixture modeling for mutational signature discovery. PubMed DOI PMC

Senkin, S. MSA: reproducible mutational signature attribution with confidence based on simulations. PubMed DOI PMC

Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. PubMed DOI PMC

Tate, J. G. et al. COSMIC: the catalogue of somatic mutations in cancer. PubMed DOI PMC

Díaz-Gay, M. et al. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment. PubMed DOI PMC

Alexander, D. H., Novembre, J. & Lange, K. Fast model-based estimation of ancestry in unrelated individuals. PubMed DOI PMC

Fairley, S., Lowy-Gallego, E., Perry, E. & Flicek, P. The International Genome Sample Resource (IGSR) collection of open human genomic variation resources. PubMed DOI PMC

R Core Team.

Wickham, H., François, R., Henry, L., Müller, K. & Vaughan, D. dplyr: a grammar of data manipulation. dplyr.tidyverse.org/ (2023).

Wickham, H., Vaugan, D. & Girlich, M. tidyr: tidy messy data. tidyr.tidyverse.org/ (2024).

Wickham, H. stringr: simple, consistent wrappers for common string operations. stringr.tidyverse.org/ (2023).

Heinze, G., Ploner, M., Jiricka, L. & Steiner, G. logistf: Firth’s bias-reduced logistic regression. 10.32614/CRAN.package.logistf (2003).

Kuhn, M., Vaughan, D. & Hvitfeldt, E. yardstick: tidy characterizations of model performance. yardstick.tidymodels.org (2024).

Wickham, H. ggplot2: create elegant data visualisations using the grammar of graphics. ggplot2.tidyverse.org/ (2016).

Slowikowski, K. ggrepel: an R package. ggrepel.slowkow.com/ (2024).

Kassambara, A. ggpubr: ggplot2 based publication ready plots. rpkgs.datanovia.com/ggpubr/ (2023).

Brunson, J. C. & Read, Q. D. ggalluvial: alluvial plots in ggplot2. corybrunson.github.io/ggalluvial/ (2023).

Garnier, S. et al. viridis: colorblind-friendly color maps for R. sjmgarnier.github.io/viridis/ (2024).

Wilke, C. O. cowplot: streamlined plot theme and plot annotations for ggplot2. wilkelab.org/cowplot/ (2024).

Pedersen, T. patchwork: the composer of plots. patchwork.data-imaginist.com/ (2024).

Auguie, B. & Antonov, A. gridExtra: miscellaneous functions for ‘Grid’ graphics. cran.r-project.org/web/packages/gridExtra/index.html (2017).

Gu, Z., Gu, L., Eils, R., Schlesner, M. & Brors, B. circlize implements and enhances circular visualization in R. PubMed DOI

Wickham, H., Pedersen, T. L. & Seidel, D. scales: scale functions for visualization. scales.r-lib.org/ (2023).

Gu, Z., Eils, R. & Schlesner, M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. PubMed DOI

Gu, Z., Eils, R., Schlesner, M. & Ishaque, N. EnrichedHeatmap: an R/Bioconductor package for comprehensive visualization of genomic signal associations. PubMed DOI PMC

Lawrence, M. et al. Software for computing and annotating genomic ranges. PubMed DOI PMC

Antonello, A. et al. Computational validation of clonal and subclonal copy number alterations from bulk tumor sequencing using CNAqc. PubMed DOI PMC

Torrens, L. Mutographs HNC.

Geographic and age variations in mutational processes in colorectal cancer

Geographic and age-related variations in mutational processes in colorectal cancer