Abstract
Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes.
Highlights
Association studies in other case-control cohorts is warranted
This study focused on 56 single nucleotide polymorphisms (SNPs) previously reported to be associated with lung cancer risk, survival, or factors predisposing to lung cancer, i.e., chronic obstructive pulmonary disease (COPD)[31] and nicotine dependence[32]
This study focused on 56 SNPs previously reported to be associated with lung cancer in different populations, and comprised both a replication effort and an expression quantitative trait loci (eQTL) analysis
Summary
Association studies in other case-control cohorts is warranted. to go beyond statistical associations, these candidate SNPs must be investigated for their putative functional roles in lung cancer. The functional characterization of candidate SNPs from GWAS is challenging, since most of them map in non-coding regions[24] and do not exert direct effects on proteins, for example by introducing premature stop codons These “regulatory SNPs” exert their effects by modifying non-transcribed regions of the genome (e.g. gene promoters, enhancers and silencers) where they alter transcription factor binding and chromatin states, as well as untranslated regions of RNA where they affect RNA splicing[25,26]. Our finding that SNPs in the promoter of CHRNA5 altered this gene’s expression levels in normal lung tissue[27] suggested that modulation of transcriptional activity was, at least in part, responsible for the association of the 15q25 locus with lung cancer risk These results shed light on a possible functional role of these polymorphisms in lung tumorigenesis. We used eQTL analysis to look for the possible involvement of these candidate SNPs in the modulation of gene expression in non-involved lung tissue from lung adenocarcinoma patients, with the aim of identifying their mechanisms of action in lung cancer predisposition and progression
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