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 × 10-8 ) and 930 SNPs in high linkage disequilibrium (r2  > 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 unknown membrane 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.