Risk SNP-Mediated Enhancer–Promoter Interaction Drives Colorectal Cancer through Both FADS2 and AP002754.2

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 ¼ 1.26; 95% confidence interval ¼ 1.17-1.36; P ¼ 2.57 Â 10 -9 ). rs174575 acted as an allelespecific 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.

Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases

“…The effect of the already identified TFs with their binding sites affected by a nucleotide substitution on the expression of putative target genes is confirmed by siRNA-induced knockdown of the TFs [ 23 , 26 , 59 ] and/or their overexpression [ 16 , 20 , 26 , 74 ]. The same approaches are applied to detect widespread effects of rSNPs at the level of transcriptome [ 20 , 75 ].…”

“…Then the transcription levels of the selected genes are assayed [ 23 , 28 , 79 , 80 ] or a whole transcriptome analysis is performed [ 78 , 80 ]. A physical interaction between the region carrying an SNP and the potential target genes is usually confirmed with the help of Hi-C methods [ 26 , 28 , 59 , 80 ], including allele-specific chromosome conformation capture assays [ 74 ], or using available Hi-C data [ 59 , 79 , 81 ].…”

Gene signature based on B cell predicts clinical outcome of radiotherapy and immunotherapy for patients with lung adenocarcinoma

“…[36][37][38][39][40] FADS3, as a fatty acid desaturase, was located along with FADS1 and FADS2, 41 which were reported to be associated with the occurrence and development of NSCLC and colon cancer. 42,43 Promoter methylation of RUBCNL was identified as a potential biomarker for early diagnosis of cervical cancer. 44 BIRC3, baculoviral IAP repeat-containing protein 3, as an apoptosis inhibitor, was overexpressed in multiple cancers and led to development of malignant tumors.…”

“…PARP15, polymerase family member 15, was originally confirmed as a risk‐related gene in diffuse large B cell lymphomas, and might be potential predictors of hematological toxicity associated with RT for acute myeloid leukemia, cervical cancer, nasopharynx cancer, and tongue cancer 36–40 . FADS3, as a fatty acid desaturase, was located along with FADS1 and FADS2, 41 which were reported to be associated with the occurrence and development of NSCLC and colon cancer 42,43 . Promoter methylation of RUBCNL was identified as a potential biomarker for early diagnosis of cervical cancer 44 .…”

The association between polymorphisms in long non-coding RNA and lung cancer in non-smoking women

“…LncRNAs, which are polyadenylated, are larger than 200-nucleotide-long that are involved in gene expression [10][11][12]. Many studies have shown that long non-coding RNA was associated with the progression of various cancers [13][14][15][16]. Although lncRNAs in lung cancer are an emerging eld, HOTAIR, H19, ANRIL and MALAT1 have been shown to be involved in lung cancer [17][18][19][20].…”