title: Genetic variations in the transforming growth factor beta pathway as predictors of bladder cancer risk.
abstract: Bladder cancer is the fifth most common cancer in the United States, and identifying genetic markers that may predict susceptibility in high-risk population is always needed. The purpose of our study is to determine whether genetic variations in the transforming growth factor-beta (TGF-β) pathway are associated with bladder cancer risk. We identified 356 single-nucleotide polymorphisms (SNPs) in 37 key genes from this pathway and evaluated their association with cancer risk in 801 cases and 801 controls. Forty-one SNPs were significantly associated with cancer risk, and after adjusting for multiple comparisons, 9 remained significant (Q-value ≤0.1). Haplotype analysis further revealed three haplotypes within VEGFC and two haplotypes in EGFR were significantly associated with increased bladder cancer risk compared to the most common haplotype. Classification and regression tree analysis further revealed potential high-order gene-gene interactions, with VEGFC: rs3775194 being the initial split, which suggests that this variant is responsible for the most variation in risk. Individuals carrying the common genotype for VEGFC: rs3775194 and EGFR: rs7799627 and the variant genotype for VEGFR: rs4557213 had a 4.22-fold increase in risk, a much larger effect magnitude than that conferred by common genotype for VEGFR: rs4557213. Our study provides the first epidemiological evidence supporting a connection between TGF-β pathway variants and bladder cancer risk.
authors.affiliation: Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Wei
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
authors.forename: Saad
authors.initials: S
authors.lastname: Aldousari
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Maosheng
authors.initials: M
authors.lastname: Huang
authors.forename: Colin P
authors.initials: CP
authors.lastname: Dinney
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D016022:Case-Control Studies; D003710:Demography; D004843:Epistasis, Genetic; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis; D016212:Transforming Growth Factor beta / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics
chemical_list: D016212:Transforming Growth Factor beta; D042582:Vascular Endothelial Growth Factor C; C512478:EGFR protein, human; D066246:ErbB Receptors