Pathway analysis of bladder cancer genome-wide association study identifies novel pathways involved in bladder cancer development.

Meng Chen,Xifeng Wu,Jonine D Figueroa,Nathaniel Rothman,Colin P Dinney,Stephen J Chanock,Debra T Silverman,Jian Gu,David W Chang,Yuanqing Ye,Paul A Scheet,Maosheng Huang

doi:10.18632/genesandcancer.113

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 of RAPGEF1, SKP1, HERPUD1, CACNB2, CACNA1C, CACNA1S, COL4A2, SRC, and CACNA1C were associated with bladder cancer risk. Two CCNE1 variants, rs8102137 and rs997669, from cell cycle pathways showed the strongest associations; the CCNE1 signal 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.

Highlights

Urinary bladder cancer is the fourth most common cancer in men in U.S Estimates in 2015 indicate urinary bladder cancer affects 56,320 males and 17,680 females, and will lead to 16,000 deaths in the U.S [1]
A total of 781 pathways, including those from KEGG, Biocarta, and Reactome databases were included in the gene set enrichment analysis (GSEA) of bladder cancer Genome-wide association studies (GWAS) (Supplementary Figure 1)
We identified 85 possibly significant pathways associated with bladder cancer risk by Gen-Gen method alone (Supplementary Table 1), 44 significant pathways by Aligator (Supplementary Table 2), and 68 significant pathways by single nucleotide polymorphism (SNP) Ratio Test (Supplementary Table 3)

Summary

Introduction

Urinary bladder cancer is the fourth most common cancer in men in U.S Estimates in 2015 indicate urinary bladder cancer affects 56,320 males and 17,680 females, and will lead to 16,000 deaths in the U.S [1]. Bladder cancer is a heterogeneous disease attributed to many risk factors. Occupational exposure to chemicals [3, 4], genetic factors, and other environmental factors such as dietary factors, lifestyle factors, medical factors, fluid intake, contribute to bladder cancer carcinogenesis [5], some of the risk factors are inconclusive and vary in different studies. There is substantial evidence that there is an important genetic contribution to susceptibility to www.impactjournals.com/Genes&Cancer bladder cancer, initially based on familial clustering of bladder cancer. A large population based twin study evaluated the contribution of hereditary factors to the causation of various sporadic cancers and estimated the genetic contribution of bladder cancer to be roughly 30% [10]

Methods

Results

Conclusion