Abstract
Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10−7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11–1.24; P = 8.31 × 10−9). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.
Highlights
The most common risk factor for lung cancer, only about one-tenth of the smokers develop lung cancer in their lifetimes[3], which suggests that other factors play important roles in lung carcinogenesis[4]
The meta-analysis of 690,564 SNPs in long non-coding RNAs (lncRNAs) from the TRICL consortium showed that 59 SNPs were associated with lung cancer risk with a P value < 1 × 10−7, and no heterogeneity among these genome-wide association studies (GWASs) datasets was noted, except for one SNP of rs35031105 (Supplementary Table 1)
Of these 59 SNPs, 53 from 11 lncRNAs were located at the lung cancer risk-related loci 6p21.33 and 6p22.1 that have been reported previously[6,20]
Summary
The most common risk factor for lung cancer, only about one-tenth of the smokers develop lung cancer in their lifetimes[3], which suggests that other factors play important roles in lung carcinogenesis[4]. Over the past few years, genome-wide association studies (GWASs) of lung cancer have identified multiple loci associated with lung cancer risk[5,6,7,8,9,10]. SNPs in several lncRNA genes previously identified to be involved in cancer development have been reported to be associated with cancer risk, e.g. rs7763881 in the hepatocellular cancer-related HULC gene[18] and rs920778 in the gastric cancer-related HOTAIR gene[19]. These results provide some evidence for the important roles of lncRNA SNPs in carcinogenesis. We re-visited several published GWASs and evaluated the effects of lncRNA SNPs on lung cancer risk by using a large-scale meta-analysis of six previously published lung cancer GWAS datasets from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium and two additional GWAS datasets of independent Caucasian populations from Harvard University and Icelandic lung cancer study[8]
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