ASPO Abstracts
Associations of genetic variants in cis-acting elements influencing alternative splicing and lung cancer risk in European populations
Category: Molecular Epidemiology & Environment, Early Detection & Risk Prediction
Conference Year: 2018
Abstract Body:
RNA splicing, regulated by cis-acting splicing elements and trans-acting splicing factors, plays a critical role in cancer development and survival. Alternative and aberrant RNA splicing events have been reported in genes implicated in the hallmarks of cancer. In this study, we tested the hypothesis that genetic variants in cis-acting splicing elements influencing RNA splicing are associated with lung cancer risk in European populations. To this end, we performed functional prediction for SNPs with minor allele frequency (MAF) >=0.01 in the whole genome using the 1000 Genomes Project CEU populations wit the SNPinfo online SNP function prediction tool and the Ensembl Variant Effect Predictor. For SNPs predicted to regulate RNA splicing, we further assessed their correlations with RNA splicing using the summary data of 383 normal lung tissues in the GTEx database. In total, we found that 5,182 putatively functional SNPs were significantly associated with RNA splicing events in 3,884 genes (P<0.05). We then assessed the associations of these SNPs with lung cancer risk using the summary genotyping data of six published genome-wide association studies (GWASs) of 12,160 cases and 16,838 controls of European ancestry from the Transdisciplinary Research in Cancer of the Lung (TRICL)- International Lung Cancer Consortium (ILCCO). We found that 16 SNPs in 10 loci were associated with lung cancer risk after correction by false discovery rate (FDR) < 0.2. After excluding previously reported SNPs, we identified eight novel SNPs (SLC11A1 rs2276631, LOC rs58309239, JADE2 105374536 and rs329118, PDZD7 rs6584410, MYRF 198459, SH2B3 rs3184504, GGA2 rs2285521 and EARS2 rs6497671) that were associated with lung cancer risk. Taken together, our study provided preliminary evidence for associations between SNPs in cis-acting splicing elements influencing RNA splicing and lung cancer risk. Validation in additional populations and further investigation of the functions of these SNPs are warranted (Supported by DOD PC131972 and NIH CA014236).
Keywords: RNA splicing, SNP, Lung cancer, GWAS, Case-control study