A study published on 24 April 2026 in the International Journal of Oral Science has characterized a subgroup of oral cavity squamous cell carcinomas (OCSCC) that occur in individuals without exposure to established risk factors such as tobacco, alcohol, or HPV infection. The findings indicate this subgroup represents a distinct molecular subtype.
Methodology & Sample
The study was led by researchers from the International Agency for Research on Cancer (IARC/WHO) and the Cancer Research Center of Lyon (CRCL). The analysis examined 347 head and neck cancer samples from The Cancer Genome Atlas database. This sample set included:
- 253 oral cavity cancers
- 94 laryngeal cancers (used as smoking-related controls)
The research team employed mutational signature analysis and multi-omics techniques to examine DNA mutations, gene expression, and epigenetic changes.
Key Findings
Mutational ClustersThe analysis identified four distinct mutational clusters based on characteristic mutation patterns:
- Two clusters were associated with smoking and alcohol use (signatures SBS4 and SBS16).
- Two clusters were enriched for cases with no identified risk factor (NIRF).
The NIRF clusters were dominated by endogenous mutational processes, including the aging-related signature SBS1 and the APOBEC-associated signatures SBS2 and SBS13.
No mutational signatures linked to environmental carcinogens were detected in these NIRF clusters. The NIRF clusters exhibited biological heterogeneity, with one cluster driven by age-related mutations and the other by APOBEC-mediated mutagenesis.
Molecular Features of NIRF TumorsThe NIRF tumors demonstrated distinct molecular features, including:
- Unique driver gene mutations related to immune function and cell signaling
- Activation of antimicrobial and keratinization pathways
- Presence of bacterial components, confirmed histopathologically
The NIRF tumors exhibited features of immune evasion. The APOBEC-driven mutagenesis observed may indicate sensitivity to therapies targeting DNA damage response pathways.
Statements from Researchers
Dr. Jiri Zavadil (IARC/WHO) stated that the study aimed to uncover the molecular mechanisms behind NIRF OCSCC and determine if they represent a distinct subtype.
Prof. François Virard (CRCL) noted that two clusters enriched with NIRF cases were dominated by endogenous processes, suggesting that internal biological mechanisms, rather than external exposures, play a key role.
Conclusion
The study establishes NIRF OCSCC as a distinct molecular subtype driven by endogenous mutational processes, with a possible influence from the oral microbiome. The findings may lead to improved diagnostic classification and the identification of new therapeutic targets.