Whole exome sequencing-based identification of genetic variants associated with oral squamous cell carcinoma in Northern Indian population

Background: Oral squamous cell carcinoma (OSCC) constitutes a significant public health burden in India, particularly in Eastern Uttar Pradesh (EUP), where tobacco-related malignancies demonstrate exceptionally elevated prevalence. Understanding the genetic architecture underlying OSCC susceptibility in this population remains inadequately characterized. Materials and Methods: This case–control study employed whole exome sequencing (WES) on 40 samples (20 histopathologically confirmed OSCC cases and 20 matched healthy controls) from EUP. In addition, mitochondrial DNA (mtDNA) analysis was performed on 98 individuals (47 cases and 51 controls). Variant calling utilized GATK best practices, with annotation through ANNOVAR. Statistical analyses included Chi-square tests with Bonferroni correction and permutation testing. Results: The mean age of cases was 52.4 ± 12.3 years, with 85.1% male predominance. Smokeless tobacco use was documented in 68.1% of cases. WES identified case-enriched variants in NOTCH1 (p.R2156H; 15.0% cases versus 0% controls; P = 0.032), FAT1 truncating mutations (10.0% cases), and a novel USP9X frameshift. Three novel variants in the PLA2G2A, POLE, and BRIP1 genes were identified exclusively in cases. mtDNA analysis revealed significant depletion of mutation 223 in cases (53.2%) compared to controls (90.2%; χ² ² =16.74, P < 0.0001). No significant differences were observed in overall mutation burden (cases: 4.43 ± 1.67 versus controls: 4.00 ± 1.52; P = 0.28). Conclusion: This study identifies population-specific genetic variants, including novel findings in PLA2G2A, POLE, and BRIP1, alongside protective mtDNA polymorphisms in tobacco-associated OSCC within Northern India. These findings provide foundational insights for precision medicine approaches in this high-burden region.