Positional integration of lung adenocarcinoma susceptibility loci with primary human alveolar epithelial cell epigenomes.

Aim: To identify functional lung adenocarcinoma (LUAD) risk SNPs. Materials & methods: Eighteen validated LUAD risk SNPs (p <= 5 x 10(-8)) and 930 SNPs in high linkage disequilibrium (r(2) > 0.5) were integrated with epigenomic information from primary human alveolar epithelial cells. Enhancer-associated SNPs likely affecting transcription factor-binding sites were predicted. Three SNPs were functionally investigated using luciferase assays, expression quantitative trait loci and cancer-specific expression. Results: Forty-seven SNPs mapped to putative enhancers; 11 located to open chromatin. Of these, seven altered predicted transcription factor-binding motifs. Rs6942067 showed allele-specific luciferase expression and expression quantitative trait loci analysis indicates that it influences expression of DCBLD1, a gene that encodes an unknownmembrane protein and is overexpressed in LUAD. Conclusion: Integration of candidate LUAD risk SNPS with epigenomic marks from normal alveolar epithelium identified numerous candidate functional LUAD risk SNPs including rs6942067, which appears to affect DCBLD1 expression. Data deposition: Data are provided in GEO record GSE84273.