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

Chenchen Yang; Theresa Ryan Stueve; Chunli Yan; Suhn K Rhie; Daniel J Mullen; Jiao Luo; Beiyun Zhou; Zea Borok; Crystal N Marconett; Ite A Offringa

doi:10.2217/epi-2018-0003

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

Epigenomics. 2018 Sep;10(9):1167-1187. doi: 10.2217/epi-2018-0003. Epub 2018 Sep 13.

Authors

Chenchen Yang^{1

2

3}, Theresa Ryan Stueve^{1

2

3

4}, Chunli Yan^{1

2

3}, Suhn K Rhie^{1

2

3}, Daniel J Mullen^{1

2

3}, Jiao Luo^{2

5}, Beiyun Zhou^{3

5

6}, Zea Borok^{2

3

5

6}, Crystal N Marconett^{1

2

3}, Ite A Offringa^{1

2

3}

Affiliations

¹ Department of Surgery, University of Southern California, CA 90089, USA.
² Department of Biochemistry & Molecular Medicine, University of Southern California, CA 90089, USA.
³ Norris Comprehensive Cancer Center, University of Southern California, CA 90089, USA.
⁴ Department of Preventive Medicine, University of Southern California, CA 90089, USA.
⁵ Department of Medicine, Division of Pulmonary & Critical Care & Sleep Medicine, University of Southern California, CA 90089, USA.
⁶ Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, CA 90089, USA.

Abstract

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.

Keywords: DCBLD1; FAIRE; SNP; alveolar epithelial cells; eQTL; enhancer; epigenomics; lung adenocarcinoma; rs6942067.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenocarcinoma / genetics*
Alveolar Epithelial Cells / cytology
Alveolar Epithelial Cells / metabolism*
Enhancer Elements, Genetic / genetics*
Epigenesis, Genetic*
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Humans
Linkage Disequilibrium
Lung Neoplasms / genetics*
Male
Membrane Proteins / biosynthesis
Membrane Proteins / genetics*
Middle Aged
Polymorphism, Single Nucleotide*
Quantitative Trait Loci

Substances

DCBLD1 protein, human
Membrane Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding