Polymorphisms in mitotic checkpoint-related genes can influence survival outcomes of early-stage non-small cell lung cancer

Abstract

This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) in mitotic checkpoint-related genes and clinical outcomes of surgically resected non-small cell lung cancer (NSCLC). A total of 766 patients with NSCLC who underwent curative surgery were enrolled. 73 SNPs form 25 mitotic checkpoint-related genes were genotyped and their associations with survival outcomes were analyzed. Among the 73 SNPs evaluated, BUB3 rs7897156C>T and AURKB rs1059476G>A were significantly associated with overall survival under a recessive model (adjusted hazard ratio [aHR] = 1.58, 95% confidence interval [CI] = 1.07–2.33, P = 0.02 and aHR = 0.64, 95% CI = 0.41–0.99, P = 0.05, respectively). PTTG1 rs1895320T>C and RAD21 rs1374297C>G were associated with worse disease-free survival (under a recessive model, aHR = 2.46, 95% CI = 1.43–4.23, P = 0.001 and under a codominant model, aHR = 1.18, 95% CI = 1.01–1.38, P = 0.04, respectively). In the functional study, relative luciferase activities were higher at the BUB3 rs7897156T allele compared to that at the C allele in H1299 and A549 cell lines ( P = 0.02 and 0.003, respectively). BUB3 mRNA expression was also higher in the rs7897156CT or TT genotypes than in the rs7897156CC genotype ( P = 0.04). The three-dimensional model of Aurora kinase indicates that AURKB rs1059476G>A leads to increased hydrophobicity of Aurora kinases B. We found that four SNPs of mitotic checkpoint-related genes were associated with survival outcomes in patients with surgically resected NSCLC. Particularly, our results suggest that BUB3 rs7897156C>T and AURKB rs1059476G>A are funcitional SNPs.