Genomic Landscape of Oral Squamous Cell Carcinoma in Never Smokers and Never Drinkers

George, Sinumol; Anantharaman, Devasena

doi:10.31557/APJCP.2026.27.6.2323

Genomic Landscape of Oral Squamous Cell Carcinoma in Never Smokers and Never Drinkers

Document Type : Research Articles

Authors

Sinumol George ¹^{, 2}
Devasena Anantharaman ¹^{, 2}

¹ Cancer research laboratory-13, BRIC- Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.

² Regional Centre for Biotechnology, Faridabad, Haryana, India.

10.31557/APJCP.2026.27.6.2323

Abstract

Objective: To identify the mutational landscape of oral cancers of unknown etiology by leveraging publicly available datasets. Methods: Oral cancer mutation data in TCGA were accessed to identify never-smoking and never-alcohol-drinking subjects with genomic, epigenomic, and transcriptomic data. Habit-free participants within published individual whole-exome sequencing studies of oral cancer were examined as the replication dataset. Results: Somatic mutation analysis of 42 habit-free TCGA oral cancer subjects revealed MUC16 and MUC5B as recurrent mutational targets in 30% of all habit-free oral cancers; the highest after previously reported oral cancer genes such as TP53, CASP8, CDKN2A, NOTCH1. Comparison against other habit-free oral cancers not only confirmed these observations but also identified additional mucin genes as frequent mutational targets, supporting their potential causal role. Gene expression and immune fraction analysis of bulk transcriptomic data showed that habit-free oral cancers were enriched for the expression of mesenchymal genes and in T-regulatory cells. Conclusion: Together, these data suggest that mucin genes, specifically MUC16 and MUC5B, are important for oral carcinogenesis in the absence of tobacco and alcohol. These results are relevant given the increasing clinical utility of mucins as druggable targets in cancer, particularly MUC16.

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