Population-specific genomic risk markers for oral and maxillofacial malignancies in a high tobacco-exposure cohort from Eastern Uttar Pradesh, India.

Oral squamous cell carcinoma (OSCC) dominates oral malignancies in Eastern Uttar Pradesh, India, driven by high smokeless tobacco use and late-stage presentations causing substantial mortality. Hence, this case-control study integrated mitochondrial DNA (mtDNA) profiling and whole exome sequencing (WES) in 98 participants (47 OSCC cases, 51 matched controls) from this high-burden region. mtDNA analysis revealed significant depletion of the 16223C polymorphism in cases (53.2% vs 90.2% controls; χ2=16.74, p=0.0001), indicating potential protective effects against OSCC development. WES identified case-enriched driver variants, including NOTCH1 p.R2156H (15.0% cases) and truncating FAT1 mutations (10.0% cases), highlighting key oncogenic pathways. These findings advance precision oncology by establishing population-specific genomic markers for risk-stratification and targeted prevention of tobacco-related OSCC in Northern India.