Endothelial nitric oxide synthase polymorphisms/haplotypes are strong modulators of oral cancer risk in Serbian population

Oral carcinoma is the sixth most common malignancy worldwide, with survival rates of approximately 50%. The major type of oral cancer, present in 90% of the cases, is oral squamous cell carcinoma (OSCC). The genetic background predisposing an individual to OSCC is complex and largely unknown. Studies have suggested that endothelial nitric oxide synthase (eNOS) gene polymorphisms modulate the cancer risk, prompting us to assess the impact of three functional eNOS gene polymorphisms on OSCC risk. The present study included 50 patients with OSCC and 110 controls. Polymerase chain reaction and restriction fragment length polymorphism analysis were used for genotyping of single-nucleotide polymorphisms −786 T/C (rs2070744) and 894 G/T (rs1799983) and variable number of tandem repeats (VNTR) intron 4b/a polymorphism. Homozygous carriers of −786 T/C and intron 4b/a VNTR variant alleles paired with a significant increase of oral cancer risk [odds ratio (OR): 3.63, 95% confidence interval (CI): 1.08-12.21; P = 0.045 and OR: 11.29, 95% CI: 2.71-47.11; P < 0.001, respectively]. When combined, CC and 4b4a genotypes together led to a 21-fold OSCC risk increase (OR: 21, 95% CI: 2.07-213.29; P = 0.006). Haplotype analysis showed that the C-G-4b haplotype conferred an 11-fold increase in OSCC risk. In conclusion, eNOS polymorphisms considerably influence levels of OSCC risk in the Serbian population.