title: Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development.
abstract: Genome-wide association studies (GWAS) are designed to identify individual regions associated with cancer risk, but only explain a small fraction of the inherited variability. Alternative approach analyzing genetic variants within biological pathways has been proposed to discover networks of susceptibility genes with additional effects. The gene set enrichment analysis (GSEA) may complement and expand traditional GWAS analysis to identify novel genes and pathways associated with bladder cancer risk. We selected three GSEA methods: Gen-Gen, Aligator, and the SNP Ratio Test to evaluate cellular signaling pathways involved in bladder cancer susceptibility in a Texas GWAS population. The candidate genetic polymorphisms from the significant pathway selected by GSEA were validated in an independent NCI GWAS. We identified 18 novel pathways (P< 0.05) significantly associated with bladder cancer risk. Five of the most promising pathways (P≤ 0.001 in any of the three GSEA methods) among the 18 pathways included two cell cycle pathways and neural cell adhesion molecule (NCAM), platelet-derived growth factor (PDGF), and unfolded protein response pathways. We validated the candidate polymorphisms in the NCI GWAS and found variants ofRAPGEF1, SKP1, HERPUD1, CACNB2, CACNA1C, CACNA1S, COL4A2, SRC, andCACNA1Cwere associated with bladder cancer risk. TwoCCNE1variants, rs8102137 and rs997669, from cell cycle pathways showed the strongest associations; theCCNE1signal at 19q12 has already been reported in previous GWAS. These findings offer additional etiologic insights highlighting the specific genes and pathways associated with bladder cancer development. GSEA may be a complementary tool to GWAS to identify additional loci of cancer susceptibility.
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Scheet
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Maosheng
authors.initials: M
authors.lastname: Huang
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Chang
authors.affiliation: Department of Urology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jonine D
authors.initials: JD
authors.lastname: Figueroa
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
keywords: GWAS; bladder cancer; gene set enrichment analysis; pathway analysis; susceptibility loci