Abstract
Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17-1.36; P = 2.57 × 10-9). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer-promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth in vitro and in vivo by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology. SIGNIFICANCE: This study provides an oncogenic regulatory circuit among several oncogenes including E2F1, FADS2, and AP002754.2 underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer-promoter interaction loops. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1804/F1.large.jpg.
Highlights
Colorectal cancer is a leading cancer-related cause of death worldwide [1]
We found that the SNP rs174575 located in the first intron of FADS2 is enriched within active histone modification peaks (H3K4me1, H3K4me3, and H3K27ac) and open chromatin accessibility (DNase-seq and ATAC-seq peaks; Fig. 1B)
This variant has statistically significant expression quantitative trait loci (eQTL) with both FADS2 and long noncoding RNA (lncRNA) AP002754.2 expression levels in the Cancer Genome Atlas (TCGA) colorectal cancer samples (Fig. 1C), which are in line with the results from our own colorectal cancer samples (Fig. 1D) and the characteristics of own colorectal cancer tissues are presented in the Supplementary Table S4
Summary
Colorectal cancer is a leading cancer-related cause of death worldwide [1]. In China, colorectal cancer is the third most commonly diagnosed cancer and the fifth leading cause of cancer-related deaths, causing a major public health burden [2, 3]. Convincing evidence is noted that some environmental exposures, including alcohol intake, tobacco smoking, overnutrition, and obesity could contribute to the risk of colorectal cancer [4]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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