title: Genetic variants in TGF-β pathway are associated with ovarian cancer risk.
abstract: The transforming growth factor-β (TGF-β) signaling pathway is involved in a diverse array of cellular processes responsible for tumorigenesis. In this case-control study, we applied a pathway-based approach to evaluate single-nucleotide polymorphisms (SNPs) in the TGF-β signaling pathway as predictors of ovarian cancer risk. We systematically genotyped 218 SNPs from 21 genes in the TGF-β signaling pathway in 417 ovarian cancer cases and 417 matched control subjects. We analyzed the associations of these SNPs with ovarian cancer risk, performed haplotype analysis and identified potential cumulative effects of genetic variants. We also performed analysis to identify higher-order gene-gene interactions influencing ovarian cancer risk. Individual SNP analysis showed that the most significant SNP was SMAD6: rs4147407, with an adjusted odds ratio (OR) of 1.60 (95% confidence interval [CI], 1.14-2.24, P = 0.0066). Cumulative genotype analysis of 13 SNPs with significant main effects exhibited a clear dose-response trend of escalating risk with increasing number of unfavorable genotypes. In gene-based analysis, SMAD6 was identified as the most significant gene associated with ovarian cancer risk. Haplotype analysis further revealed that two haplotype blocks within SMAD6 were significantly associated with decreased ovarian cancer risk, as compared to the most common haplotype. Gene-gene interaction analysis further categorized the study population into subgroups with different ovarian cancer risk. Our findings suggest that genetic variants in the TGF-β signaling pathway are associated with ovarian cancer risk and may facilitate the identification of high-risk subgroups in the general population.
authors: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors: Jikai
authors: J
authors: Yin
authors: Karen
authors: K
authors: Lu
authors: Jie
authors: J
authors: Lin
authors: Lei
authors: L
authors: Wu
authors: Michelle A T
authors: MA
authors: Hildebrandt
authors: David W
authors: DW
authors: Chang
authors: Larissa
authors: L
authors: Meyer
authors: Xifeng
authors: X
authors: Wu
authors: Dong
authors: D
authors: Liang
mesh_terms: D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051905:Smad6 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
chemical_list: C497802:SMAD6 protein, human; D051905:Smad6 Protein; D016212:Transforming Growth Factor beta