Mutational signature-based classification uncovers emerging oral cancer subtypes with distinct molecular patterns

Scientists from the International Agency for Research on Cancer (IARC) and partner institutions have uncovered detailed molecular subtypes of oral cancer in patients without identified risk factors, challenging the traditional risk-factor model. The researchers identified two distinct subgroups in these patients; one signature was enriched in younger patients, and one was enriched in patients with mobile tongue cancers, a cancer type of which the incidence is increasing globally. The results were published in the International Journal of Oral Science.

The new study presents a comprehensive molecular analysis of oral cavity squamous cell carcinomas (OCSCC), focusing on those arising in the mobile tongue in patients who do not exhibit the traditional risk factors, i.e. non-smoking, non-drinking, and human papillomavirus (HPV)-negative. The study points to the involvement of endogenous mutational processes (clock-like and APOBEC enzyme mutagenesis), unique driver mutations, DNA methylation patterns, and activation of microbial and immune-related signatures as potential drivers of disease.

The findings highlight a rising global burden of oral tongue cancers in patients without known risk factors and reveal previously uncharacterized disease subtypes. This improves understanding of distinct oral cancer origins and opens up new avenues for prevention, diagnosis, and targeted disease management.

Deneuve S, Fervers B, Bruno JS, Bach E, Senkin S, Goldman-Lévy G, et al.
Mutational signature-based classification uncovers emerging oral cancer subtypes with distinct molecular patterns
Int J Oral Sci. Published online 24 April 2026;
https://doi.org/10.1038/s41368-026-00437-4

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