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Identification of Functional Lung Adenocarcinoma Susceptibility Loci through Positional Integration with Human Alveolar Cell Epigenomes

ABSTRACT: Lung adenocarcinoma (LUAD) is the predominant lung cancer subtype. To date, 15 single nucleotide polymorphisms (SNPs) have been reproducibly associated with LUAD susceptibility. However, as most SNPs identified in genome-wide association studies (GWAS) are not located in the coding regions of genes and are co-inherited with hundreds of SNPs in linkage disequilibrium (LD), mechanistic links to disease outcomes remain largely unexplored. We hypothesized that some SNPs increase LUAD risk by affecting enhancers of gene transcription in alveolar epithelial cells (AECs), the purported cells of origin for LUAD. Forty-six LUAD risk-associated SNPs mapped to putative AEC enhancers, and 11 of these were located in FAIRE peaks. Of those, seven were predicted to form transcription factor binding motifs. For four of these, ChIPseq data confirmed the binding of the predicted transcription factors. We chose rs452384, rs6942067 and rs11364096 for functional validation. The reference (risk) allele for rs452384 forms an NKX2-1 binding site that is disrupted by the alternate allele, elicited a 42% increase in activity in H1648 LUAD cells relative to the alternative allele (P = 6.7 x 10-3), and was associated with elevated TERT levels in esophageal tissue (P = 6 x 10-8). The reference (risk) allele for rs6942067 forms an EP300 binding site disrupted by the alternate allele, elicits a 94% increase in enhancer activity relative to the alternative allele in H1648 LUAD cells (P = 2.7 x 10-2), and was associated with higher expression of potential oncogene DCBLD1 in blood (P = 5.2 x 10-16). Lastly, the alternate (risk) allele for rs11364096 disrupts binding sites for FOXA1, HDAC2 and SP1, elicits a 32% decrease in enhancer activity in A549 LUAD cells relative to the reference allele (P = 5.7 x 10-3), and LUAD data from The Cancer Genome Atlas indicates that this SNP is associated with altered expression in LUAD of four genes on other chromosomes. Our analyses provide possible mechanisms for the genetic susceptibility to LUAD, with the identification of three strong functional SNP candidates that appear to affect AEC enhancers. Further investigation of these enhancers and their target genes may ultimately yield more effective and personalized strategies for LUAD risk assessment, prevention and treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84273 | GEO | 2019/03/18

REPOSITORIES: GEO

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Project description:Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations- we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r^2≥0.5. Greater than 88% of the 727 SNPs fall within putative enhancers, many of which alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid in the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancer regions, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r^2=0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process. ChIP-seq analysis of H3K27Ac in LNCaP charcoal-stripped serum, H3K27Ac in LNCaP charcoal-stripped serum +DHT, TCF7L2 in LNCaP

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Identification of Functional Lung Adenocarcinoma Susceptibility Loci through Positional Integration with Human Alveolar Cell Epigenomes

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