Abstract 2650: A combined bioinformatics and GWAS approach identifies a functional 3′UTR insertion/deletion in YES1 associated with bladder cancer risk

Abstract

Abstract Bladder cancer (BC) is diagnosed in over 70,000 individuals each year and its incidence is rising. There is a need for biomarkers to identify those at high risk, as well as for early detection. Large genome-wide association studies have identified multiple susceptibility loci; however, individually and combined, these variants only explain a small portion of the variation in BC risk. One possibility to explain the missing heritability is the effect of small insertions and deletions (INDELs). Because of the nature of these variations, they have a high likelihood for functional effects. Therefore, the purpose of study was to determine whether common INDELs are associated with BC risk. We retrieved 0.73 million INDELs and 7.72 million single nucleotide polymorphisms (SNPs) from the 1000 Genomes Pilot Project. Tagging-SNPs were identified for 0.48 million of these INDELs with r2 > 0.80 by PLINK. We then evaluated each tagging-SNP for association with BC risk in 969 BC cases and 957 controls. Using this approach, 5,110 INDELs were shown to be associated with BC risk (P < 0.05). We next focused on potentially functional INDELs located in exons, 3′ UTRs, 5′ UTRs or promoters. Approximately 50 INDELs fit this criterion, with a 2 basepair INDEL rs56342716 (-/AT) located in the 3′ UTR of YES1, a src kinase oncogene, being highly significant. The tagging-SNP for this INDEL, rs3786347, was associated with a 1.27-fold increase in BC risk (OR 1.27, 95% CI, 1.10-1.43, P = 6.08x10−4). These results were confirmed by direct genotyping of the INDEL in 822 BC cases and 802 healthy controls (OR 1.20, 95% CI, 1.04-1.38, P = 0.01). Reporter gene assay results revealed that the variant allele (AT) of rs56342716 disrupted the inhibitory effects of three microRNAs (miR-548e, miR-548f, and miR-548a-3p), providing a potential biological mechanism for the association with BC risk through increased YES1 levels. Together, these results provide evidence supporting a connection between a functional INDEL and BC risk while implicating YES1 in bladder cancer pathogenesis through a microRNA-mediated mechanism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2650. doi:1538-7445.AM2012-2650