78 Quick summary: Advanced genomic data published in April 2026 demonstrates that oral cancers developing in individuals without tobacco or alcohol exposure represent a distinct molecular subtype driven by internal age related mechanisms and biological processes rather than external carcinogens. Multi omics analyses revealed that these specific tumours exhibit unique driver mutations and distinct microbial features, suggesting that variations in the oral microbiome and internal cellular changes play a direct role in cancer development. These findings carry vital implications for healthcare practice and public policy, providing clinical pathways towards precision medicine and targeted therapies that can combat immune evasion and improve long term survival outcomes for non smoking cancer patients. Head and neck cancers, particularly younger individuals in the oral cavity, have historically been attributed to well-defined aetiological factors such as tobacco exposure, alcohol consumption, and infection with oncogenic strains of Human papillomavirus. These factors are known to drive the majority of oral cavity squamous cell carcinomas (OCSCC), a major subtype of head and neck cancers. However, an increasing proportion of OCSCC cases are being diagnosed in individuals who lack exposure to these established risk factors, particularly younger individuals and women. Despite these changing patterns, the causes of OCSCC in this group remain poorly understood, highlighting the need for further research. Researchers conducted this study to better understand this subgroup of oral cancers, referred to as NIRF (No Identified Risk Factor) OCSCC. The study was led by lead author from the International Agency for Research on Cancer (IARC) branch of the World Health Organisation in France, and Professor François Virard of the Cancer Research Centre of Lyon.. Dr Zavadil explains the motivation behind this study: “We aimed to uncover the molecular mechanisms driving these cancers and to determine whether they represent a distinct subtype with unique biological characteristics. Given that traditional carcinogenic exposures could not explain these cases, we sought to explore whether internal processes or alternative external influences might be responsible.” The study was published in the International Journal of Oral Science on 24th April 2026. The study utilised large-scale public cancer datasets from The Cancer Genome Atlas. After rigorous quality filtering, the researchers analysed 347 head and neck cancer samples, including 253 oral cavity cancers and 94 laryngeal cancers used as smoking-related controls. Advanced genomic techniques and multi-omics analyses were employed to examine DNA mutations, gene expression, and epigenetic changes. A key methodological approach involved the identification of mutational signatures, which are characteristic patterns of mutations that reflect the underlying processes causing DNA damage. By clustering tumours based on these signatures, researchers were able to stratify patients into biologically meaningful groups. The analysis revealed four distinct mutational clusters. Two were strongly linked to known risk factors such as smoking and alcohol use, characterised by signatures like SBS4 and SBS16. Tobacco-related mutations varied by anatomical site, with laryngeal cancers showing a higher mutation burden than oral cancers, highlighting tissue-specific responses to carcinogens. “We identified two clusters enriched with NIRF cases. They were dominated by endogenous processes, particularly the ageing-related SBS1 signature and APOBEC-associated signatures (SBS2 and SBS13), suggesting that internal biological mechanisms, rather than external exposures, play a key role in NIRF OCSCC,” says Professor Virard. Importantly, no mutational signatures linked to known environmental carcinogens were identified in the NIRF tumour clusters, even though they showed biological heterogeneity, with one primarily driven by age-related mutations and the other by APOBEC-mediated mutagenesis. Further analyses revealed that NIRF tumours possess distinct molecular features, including unique driver gene mutations linked to immune function and cell signalling. Gene expression analysis indicated activation of antimicrobial and keratinisation pathways, and the presence of bacterial components, histopathologically confirmed by the researchers, suggested a potential role of the oral microbiome in tumour development. Clinically, these findings have important implications. NIRF tumours exhibited features of immune evasion, including alterations in antigen presentation pathways, which could potentially affect responses to immune checkpoint therapies. At the same time, APOBEC-driven mutagenesis points to potential sensitivity to therapies targeting DNA damage response pathways, suggesting possible future opportunities for precision medicine approaches. Overall, this study significantly refines our understanding of oral cancer by establishing NIRF OCSCC as a distinct molecular subtype. It highlights the importance of endogenous mutational processes, demonstrates site-specific effects of traditional risk factors, and suggests a possible contribution of microbial influences. In conclusion, oral cancers arising in the absence of known risk factors represent a unique disease entity with distinct biological drivers. These findings pave the way for future research into their aetiology, improve diagnostic classification, and open new avenues for targeted and more effective therapeutic strategies.