The complexity of tobacco smoke-induced mutagenesis in head and neck cancer
Laura Torrens, Sarah Moody, Ana Carolina de Carvalho, Mariya Kazachkova, Behnoush Abedi‐Ardekani, Saamin Cheema, S. Senkin, Thomas Cattiaux, Ricardo Cortez Cardoso Penha, Joshua Atkins, Valérie Gaborieau, Priscilia Chopard, Christine Carreira, Ammal Abbasi, Erik N. Bergstrom, Raviteja Vangara, Jingwei Wang, Stephen Fitzgerald, Calli Latimer, Marcos Díaz‐Gay, David Jones, Jon W. Teague, Felipe Ribeiro Pinto, Luiz Paulo Kowalski, Jerry Polesel, Fabiola Giudici, José Carlos de Oliveira, Παγώνα Λάγιου, Areti Lagiou, Marta Vilensky, Dana Mateș, Ioan Nicolae Mateș, Lídia Maria Rebolho Batista Arantes, Rui Manuel Reis, José Roberto Vasconcellos De Podestá, Sandra Ventorin von Zeidler, Ivana Holcátová, María Paula Curado, Cristina Canova, Elenora Fabianova, Paula A. Rodríguez‐Urrego, Laura Humphreys, Ludmil B. Alexandrov, Paul Brennan, Michael R. Stratton, Sandra Pérdomo
Abstract
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.