title: Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk.
abstract: BACKGROUND
  The Wnt/β-catenin signaling pathway plays a key role in stem cell maintenance in the colorectum. Rare high-penetrance genetic mutations in components of this pathway result in familial colorectal cancer, yet the impact of common, germline variants remains unknown.
  
  
  METHODS
  We assessed 172 variants in 26 genes from the Wnt/β-catenin pathway in 809 colorectal cancer cases and 814 healthy controls, followed by replication of the top findings in another 691 cases and 775 controls. In silico informatic tools were used to predict functional effects of variants.
  
  
  RESULTS
  Eighteen SNPs in the pathway were significantly associated with colorectal cancer risk (P < 0.05) in the discovery phase. We observed a significant dose-response increase in colorectal cancer risk by number of risk genotypes carried (P = 4.19 × 10(-8)). Gene-based analysis implicated CSNK1D (P = 0.014), FZD3 (P = 0.023), and APC (P = 0.027) as significant for colorectal cancer risk. In the replication phase, FZD3:rs11775139 remained significantly associated with reduced risk with a pooled OR of 0.85 [95% confidence interval (CI), 0.76-0.94, P = 0.001]. Although borderline significant in the replication population, APC:rs2545162 was highly significant in the pooled analysis-OR, 1.42; 95% CI, 1.16-1.74; P = 0.00085. Functional assessment identified several potential biologic mechanisms underlying these associations.
  
  
  CONCLUSIONS
  Our findings suggest that common germline variants in the Wnt/β-catenin pathway may be involved in colorectal cancer development.
  
  
  CONCLUSIONS
  These variants may be informative in colorectal cancer risk assessment to identify individuals at increased risk who would be candidates for screening.
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas. mhildebr@mdanderson.org.
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Reyes
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Moubin
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Son V
authors.initials: SV
authors.lastname: Nguyen
authors.affiliation: Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Hawk
authors.affiliation: Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D015179:Colorectal Neoplasms / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D012306:Risk; D015398:Signal Transduction; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
chemical_list: D051176:beta Catenin
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