Abstract 6613: Understanding the causes of head and neck cancer using mutational signature analysis

Abstract The geographical incidence of head and neck cancer (HNC) is heterogeneous, reflecting the prevalence of its main risk factors. Tobacco, either alone or combined with alcohol, is the predominant cause of HNC, while the potential of alcohol as an independent carcinogen is uncertain. Moreover, the etiology remains unknown for ~28% of cases. In this study, we used mutational signature analysis to 1) track the exposure to known and putative risk factors for HNC across multiple geographical regions and subsites, 2) evaluate whether an alcohol signature is present in HNC, and 3) assess its interaction with tobacco or other risk factors. Whole-genome sequencing data was generated from 265 HNC cases from retrospective HNC studies in Europe and South America with available lifestyle and environmental exposure data. Mutational and copy number (CN) signatures were extracted with SigProfilerExtractor and decomposed into COSMIC reference signatures. Associations between the mutational signatures and epidemiological or molecular data were assessed using multivariate regression analysis. The analysis revealed known and previously unreported signatures of endogenous and exogenous exposures. APOBEC-driven signatures (SBS2, SBS13) were identified in 97% (258/265) of cases. We observed differences in tobacco-related mutagenesis across anatomical subsites. While known tobacco signatures (SBS4, SBS92, DBS2, and ID3) were found in larynx cases, the novel signature SBS1536I was enriched in oral cavity cases from ever-smokers, which suggests a site-specific mutagenic effect from different tobacco carcinogens. Furthermore, we demonstrate that signatures associated with alcohol consumption (SBS16, DBS4, and ID11) were enriched in cases exposed to both tobacco and alcohol, indicating an interaction between the two. We also extracted signatures indicative of ultraviolet (UV) light exposure (SBS7a-c, DBS1, and ID13) in cases from the inner lip, tongue, and floor of the mouth, implying a role of UV exposure in oral cavity carcinogenesis. Finally, hierarchical clustering analysis revealed three distinct CN profiles in HNC, each linked to different risk factors and driver mutations: 1) A CN-rich polyploid cluster associated with tobacco smoking and CN signatures of chromosomal instability, including one novel signature (CN48G) enriched in samples from South America, 2) a CN-rich diploid cluster comprising cases related to both tobacco and human papillomavirus infection; and 3) a CN-neutral cluster enriched in samples with unknown etiology. This study uncovers APOBEC signaling, tobacco, alcohol, and potentially UV light exposure, as potent mutagenic agents in HNC. Our findings suggest that the mutational impact of tobacco in HNC is tissue-specific, and that tobacco may enhance the oncogenic effects of alcohol. Finally, the CN profile in HNC is strongly influenced by exposure to risk factors and driver mutations in the tumors. Citation Format: Laura Torrens, Sarah Moody, Carol De Carvalho, Sergey Senkin, Saamin Cheema, Mariya Kazachkova, Valerie Gaborieau, Behnoush Abedi-Ardekani, Ricardo Cortez Cardoso Penha, Joshua Atkins, Priscilia Chopard, Jingwei Wang, Stephen Fitzgerald, Calli Latimer, Christine Carreira, Thomas Cattiaux, Marcos Diaz-Gay, Laura Humphreys, Ludmil B. Alexandrov, Michael R. Stratton, Sandra Perdomo, Paul Brennan, HEADSpAcE consortium. Understanding the causes of head and neck cancer using mutational signature analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6613.