Association between Genetic Variants in Pre-MicroRNAs and Survival of Early-Stage NSCLC

MicroRNAs (miRNAs) are an abundant class of small non–protein-coding RNAs that function as negative gene regulators. Recent evidence indicates that altered miRNA expression plays an important role in the initiation and progression of lung cancer. Single nucleotide polymorphisms (SNPs) in pre-miRNAs could alter miRNAs processing, or expression, and hence, could influence the prognosis of lung cancer. To test this hypothesis, we evaluated the effects of four SNPs in pre-miRNAs (pre-miR-146a rs2910164, pre-miR-149 rs2292832, pre-miR-196a rs11614913, and pre-miR-499 rs3746444) on the survival outcomes of patients with early-stage non–small-cell lung cancer (NSCLC). Three hundred sixty-three patients with surgically resected NSCLC were enrolled. The four SNPs were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. Of the four SNPs examined, the pre-miR-149 rs2292832T>C and pre-miR-196a rs11614913C>T were found to be significantly associated with OS and DFS. The rs2292832 TC or CC genotype exhibited a significantly better OS and DFS compared with the rs2292832 TT genotype (adjusted hazard ratio [aHR] for OS, 0.66; 95% confidence interval [CI], 0.47–0.92; p = 0.01 and aHR for DFS, 0.64; 95% CI, 0.48–0.87; p = 0.004). For the pre-miR-196a rs11614913C>T, patients with the CT or TT genotype had a significantly better OS and DFS than those with the CC genotype (aHR for OS, 0.70; 95% CI, 0.49–0.99; p = 0.05 and aHR for DFS, 0.66; 95% CI, 0.48–0.90; p = 0.01). When the two SNPs were combined, OS and DFS improved in a dose-dependent manner as the number of good genotypes increased (p = 0.002 and 0.0001, respectively). These results suggest that miR-149 and miR-196a may be involved in the pathogenesis of NSCLC, and that rs2292832 and rs11614913 can be used as prognostic markers for patients with surgically resected early-stage NSCLC.