Abstract 1667: Pathway analysis of bladder cancer genome-wide association study identifies several novel pathways involved in bladder cancer development

Abstract

Abstract Recent genome-wide association studies (GWAS) have identified multiple genetic variants associated with bladder cancer risk but only explain a small fraction of the inherited variability. A recurring problem in traditional GWAS analysis (i.e., single-SNP analysis) is the lack of consideration of biological pathways that contains network of genes with subtle, undetectable effect at the single SNP or single gene level. Application of innovative secondary analyses focusing on genes and pathways will complement and expand traditional GWAS analysis and identify novel genes and pathways that are associated with bladder cancer risk. We used the genome-wide scan data from MD Anderson's bladder cancer case control study to identify cellular signaling pathways involved in bladder cancer tumorigenesis. Gene set enrichment analysis (GSEA) was applied as a secondary analysis of our previous bladder cancer GWAS data. GSEA can detect subtle effects of multiple SNPs in the same gene set, and multiple genes in the same biological pathway, which are often missed in traditional GWAS analysis. Using three GSEA approaches (Gen-Gen, Aligator, and SNP Ratio Test), we consistently identified 18 pathways significantly associated with bladder cancer risk. The top pathways included two cell cycle pathways involved in the G1/S transition (PGenGen: 0.001, PAligator: 0.001, PSRT: 0.002), neural cell adhesion molecule (NCAM) pathway (PGenGen:<0.001, PAligator: 0.020, PSRT: 0.014), platelet-derived growth factor (PDGF) induced intracellular pathway (PGenGen: <0.001, PAligator: 0.026, PSRT: 0.006) and unfolded protein response pathway (PGenGen: 0.007, PAligator: 0.001, PSRT: <0.001). We identified that CCNE1 rs8110447 and rs8102137 were the most significant SNPs and gene in the two cell cycle pathways. As previously reported in GWAS, CCNE1 at 19q12 is a hotspot for bladder cancer susceptibility. However, other pathways with known susceptibility genes, such as those containing GSTM1, were not significant in the GSEA analysis, suggesting that this approach has identified novel biological pathways involved in bladder cancer tumorigenesis. Future studies are needed to validate in independent population. Overall, these findings contribute to a coherent understanding of the overall gene networks involved in bladder cancer susceptibility as well as offer additional etiologic insights highlighting the specific genes and pathways involved. 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 1667. doi:1538-7445.AM2012-1667