New study uncovers how tobacco and alcohol jointly drive head and neck cancer through distinct DNA damage patterns

01.04.2025 - A new international study has revealed the complex ways in which tobacco smoke causes genetic damage leading to head and neck cancer (HNC). Published in Nature Genetics, the research analyzed 265 whole-genome sequenced HNC samples from eight countries, uncovering several tobacco-associated mutational signatures—some newly identified—and clarifying the role of alcohol when combined with tobacco exposure.

The study, led by scientists at the International Agency for Research on Cancer (IARC), confirms that tobacco smoking—alone or in combination with alcohol—is the dominant cause of head and neck cancer. It identified six mutational signatures linked to tobacco exposure, including SBS4, SBS92, and the previously undescribed SBS_I, each reflecting different types of DNA alterations. These signatures were most common in larynx cancers, although variations were found across different anatomical sites, such as the oral cavity and hypopharynx, indicating tissue-specific effects of tobacco smoke.

In addition to mapping tobacco’s impact, the study examined alcohol-related mutations. Signatures such as SBS16, ID11, and DBS4 were associated with alcohol use but were predominantly observed in individuals who also smoked. This supports earlier epidemiological evidence suggesting that alcohol alone has a limited mutagenic role in HNC but acts synergistically with tobacco, increasing the mutation burden when both substances are used together.

The authors also found that tobacco use was associated with increased genomic instability, including distinctive patterns of copy number alterations—large-scale genetic changes that further drive cancer development. In contrast, HNC cases in non-smokers showed fewer such alterations and were enriched in mutations like CASP8 and HRAS, which suggest a different, less understood path to cancer in patients without known risk factors.

The findings provide a detailed molecular map of how tobacco, and to a lesser extent alcohol, contribute to the development of head and neck cancer. According to the study, “these findings enhance our understanding of the complexity and tissue specificity of tobacco mutagenesis,” and may inform future prevention efforts.

Source: The complexity of tobacco smoke-induced mutagenesis in head and neck cancer, Nature Genetics (2025). https://doi.org/10.1038/s41588-025-02134-0