Abstract 4616: Functional genomic analyses of 21q22.3 locus identify potential functional variants and candidate gene YBEY for breast cancer risk

Abstract

Abstract We have previously identified SNP rs3541811, located in the 21q22.3 locus, to be associated with breast cancer risk in Asians. However, the underlying causal functional variants and gene(s) responsible for this association are unknown. In this study, we performed functional genomic analyses to identify potential functional variants and target genes that may mediate this association. Functional annotation for SNPs highly correlated with rs3541881, using epigenetic data from the Encyclopedia of DNA Elements (ENCODE) and Roadmap projects, showed evidence of promoter and/or enhancer activities of five putative functional SNPs, including rs35418111, rs2078203, rs8134832, rs57385578, and rs8126917. These SNPs were assessed for interactions with nuclear proteins by EMSA assay. Our results showed that compared to the reference allele, alternate allele rs2078203 (A > G) significantly increased DNA-protein interactions, while an opposite trend was observed for rs35418111 (G > A). Cis-expression quantitative loci (eQTL) analysis, using data from the Genotype-Tissue Expression (GTEx) project, The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and the Shanghai Breast Cancer Study, indicated that the risk allele rs35418111 is associated with a decreased expression of the YBEY (C21or57) gene, indicating its putative oncogenic function that may contribute to breast cancer risk. The gene YBEY is a relatively uncharacterized endoribonuclease in humans, which is thought to function in rRNA cleavage and maturation, similar to its bacterial homologues. We further investigated whether YBEY may have any biological effect in human breast cancers by knocking-down YBEY gene expression using siRNA in MCF-7, T47D, and MDA-MB-231 cell lines. Transient knockdown of YBEY gene expression in three breast cancer cell lines consistently affected cell proliferation, colony formation, and migration/invasion, regardless of hormone receptor status. Our study provides support for a significant role for human YBEY gene in breast cancer pathogenesis and the association between the rs35418111/21q22.3 locus and breast cancer risk, which may be mediated through its correlated potential functional SNPs that regulate expression of the YBEY gene. Citation Format: Chris Shidal, Xiang Shu, Jie Wu, Jifeng Wang, Shuya Huang, Joshua Bauer, Xingyi Guo, Wei Zheng, Xiao-Ou Shu, Qiuyin Cai. Functional genomic analyses of 21q22.3 locus identify potential functional variants and candidate gene YBEY for breast cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4616.