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Purpose: This study was implemented to investigate the associations between SNP in mature microRNA (miRNA) sequence and lung cancer prognosis and to verify the function of those SNP.Experimental Design: Eight SNPs (rs3746444T>C in hsa-mir-499, rs4919510C>G in hsa-mir-608, rs13299349G>A in hsa-mir-3152, rs12220909G>C in hsa-mir-4293, rs2168518G>A in hsamir-4513, rs8078913T>C in hsa-mir-4520a, rs11237828T>C in hsa-mir-5579, and rs9295535T>C in hsa-mir-5689) were analyzed in a southern Chinese population with 576 patients with lung cancer, and the significant results were validated in two additional cohorts of 346 and 368 patients, respectively. A series of experiments were performed to evaluate the relevancies of those potentially functional SNPs.Results: We found that the microRNA-499 rs3746444T>C polymorphism exhibited a consistently poor prognosis for patients with lung cancer in the discovery set [HR, 1.24; 95% confidence interval (CI), 1.02-1.49; P ¼ 0.028], in the validation set I (HR, 1.31; 95% CI, 1.01-1.71; P ¼ 0.048) and in the validation set II (HR, 1.45; 95% CI, 1.12-1.86; P ¼ 0.004). The adverse effect of CT/CC variants was more remarkable in patients receiving platinum-based chemotherapy. Further functional assays demonstrated that the rs3746444C variant allele influences the expression of several cancer-related genes and affects lung cancer cells' proliferation and tumor growth in vivo and in vitro via the cisplatinum resistance.Conclusion: Our findings suggested that the rs3746444T>C polymorphism in mature miR-499 sequence could contribute to poor prognosis by modulating cancer-related genes' expression and thus involve tumorigenesis and anti-chemotherapy, which may be a useful biomarker to predict lung cancer patients' prognosis.

Recent genome-wide association studies implicated that the nicotinic acetylcholine receptors (nAChRs) are common susceptible genes of two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. We aimed to test whether the copy number variations (CNVs) in nAChRs have hereditary contributions to development of the two diseases. In two, two-stage, case-control studies of southern and eastern Chinese, a common CNV-3956 that duplicates the cholinergic receptor, nicotinic, α7 (CHRNA7) gene was genotyped in a total of 7880 subjects and its biological phenotype was assessed. The ≥ 4-copy of CNV-3956 increased COPD risk (≥4-copy vs 2/3-copy: OR = 1.44, 95% CI = 1.23-1.68) and caused poor lung function, and it similarly augmented risk (OR = 1.49, 95% CI = 1.29-1.73) and worsened prognosis (hazard ratio (HR) = 1.25, 95% CI = 1.07-1.45) of lung cancer. The ≥ 4-copy was estimated to account for 1.56% of COPD heritability and 1.87% of lung cancer heritability, respectively. Phenotypic analysis further showed that the ≥ 4-copy of CNV-3956 improved CHRNA7 expression in vivo and increased the carriers' smoking amount. The CNV-3956 of CHRNA7 contributed to increased risks and poor prognoses of both COPD and lung cancer, and this may be a genetic biomarker of the two diseases.