A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding

Abstract

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.

Identification of nine new susceptibility loci for endometrial cancer

“…For example, the most significant SNP in this meta-analysis, rs11263761 intronic in HNF1B , had an odds ratio (OR) = 1.15 (1.12–1.19; P = 3.2 × 10 −20 ), compared with OR = 1.20 (1.15–1.25; P = 2.8 × 10 −19 ) in our previous analysis 7 . The previously reported associations with intronic AKT1 SNPs (rs2498796 OR = 1.17 (1.07–1.17); P = 3.6 × 10 −8 ) 6 , 10 did not reach genome-wide significance (rs2498796 OR = 1.07 (1.03–1.11) P = 6.3 × 10 −5 , Bayes false discovery probability (BFDP) 98%) in this meta-analysis, although the risk estimate direction is consistent with our original finding.…”

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

“…The SNPs, however, also influence the silencer activity and affect YY1 siRNA, a positive regulator of AKT1. The expression of this SNP is therefore also related to the risk of EC development [53]. In a Taiwanese population, 50% of endometrial cancers displayed mutations in the PTEN gene.…”

Association between genetic polymorphisms and endometrial cancer risk: a systematic review

“…It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively 22 30. However, this association was not replicated in a larger GWAS in 2018 21.…”

“…Following careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1). 21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list.…”