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Identifying expression and DNA methylation biomarkers for lung adenocarcinoma risk in East Asia [DNA Methylation Array]

ABSTRACT: Lung adenocarcinoma (LUAD) is the most common type of lung cancer. A recent genome-wide association study (GWAS) of LUAD in East Asia reported 28 independent susceptibility variants across 25 loci and identified 2 genes whose genetically predicted expression levels are associated with LUAD risk, using an ancestry-matched lung tissue expression quantitative trait loci (eQTL) dataset. It is desirable to identify additional susceptibility loci and to understand their underlying biological mechanisms. Using an expanded GWAS of LUAD in East Asia and ancestry-matched lung tissue eQTL and DNA methylation QTL datasets, we performed transcriptome-wide association studies and DNA methylome-wide association studies simultaneously and examined the association between measured expression of genes and DNA methylation of nearby CpGs (eQTM). Genes and nearby CpGs are termed CpG–gene–LUAD trios if these three associations hold simultaneously. At Bonferroni-corrected P<0.05, we identified a new susceptibility locus (6p21.31; lead SNP rs7772643), 10 LUAD-associated genes and 86 LUAD-associated CpGs. At false discovery rate q<0.05, we identified 28 LUAD-associated genes, 220 LUAD-associated CpGs, and 45 CpG–gene–LUAD trios; among them, 43 were direction-matched regarding these three associations. These show that 23 of the known 28 susceptibility variants for LUAD in East Asia are near these genes or CpGs and MARCH3, ELF5, IKZF3, GSDMB, CCDC116, and DSP are putative novel susceptibility loci. Few of them was reported in LUAD in European populations. This study substantially advances our understanding of the etiology of LUAD in East Asia and could be useful in developing translational applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314841 | GEO | 2026/02/04

REPOSITORIES: GEO

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Project description: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.

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Identifying expression and DNA methylation biomarkers for lung adenocarcinoma risk in East Asia [DNA Methylation Array]

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