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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Geographic and age variations in mutational processes in colorectal cancer

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