Dataset Information

Germline Genetic Variants in the Wnt/?-Catenin Pathway as Predictors of Colorectal Cancer Risk.

ABSTRACT: The Wnt/?-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.We assessed 172 variants in 26 genes from the Wnt/?-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.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.Our findings suggest that common germline variants in the Wnt/?-catenin pathway may be involved in colorectal cancer development.These variants may be informative in colorectal cancer risk assessment to identify individuals at increased risk who would be candidates for screening.

SUBMITTER: Hildebrandt MA

PROVIDER: S-EPMC4779688 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk.

Hildebrandt Michelle A T MA Reyes Monica E ME Lin Moubin M He Yonggang Y Nguyen Son V SV Hawk Ernest T ET Wu Xifeng X

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20160125 3

<h4>Background</h4>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.<h4>Methods</h4>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 con ...[more]

PMID: 26809274

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Project description:BackgroundAberrant Wnt/beta-catenin pathway activation is implicated in Multiple Myeloma (MM) development, but little is known if genetic variants within this pathway contribute to MM susceptibility.MethodsWe performed a discovery candidate pathway analysis in 269 non-Hispanic white MM cases and 272 controls focusing on 171 variants selected from 26 core genes within the Wnt/beta-catenin pathway. Significant candidate variants (P < 0.05) were selected for validation in internal and external non-Hispanic white populations totaling 818 cases and 1209 controls. We also examined significant variants in non-Hispanic black and Hispanic case/control study populations to identify potential differences by race/ethnicity. Possible biological functions of candidate variants were predicted in silico.ResultsSeven variants were significantly associated with MM risk in non-Hispanic whites in the discovery population, of which LRP6:rs7966410 (OR: 0.57; 95 % CI: 0.38-0.88; P = 9.90 × 10-3) and LRP6:rs7956971 (OR: 0.64; 95 % CI: 0.44-0.95; P = 0.027) remained significant in the internal and external populations. CSNK1D:rs9901910 replicated among all three racial/ethnic groups, with 2-6 fold increased risk of MM (OR: 2.40; 95 % CI: 1.67-3.45; P = 2.43 × 10-6 - non-Hispanic white; OR: 6.42; 95 % CI: 2.47-16.7; P = 3.14 × 10-4 - non-Hispanic black; OR: 4.31; 95 % CI: 1.83-10.1; P = 8.10 × 10-4 - Hispanic). BTRC:rs7916830 was associated with a significant 37 % and 24 % reduced risk of MM in the non-Hispanic white (95 % CI: 0.49-0.82; P = 5.60 × 10-4) and non-Hispanic Black (95 % CI: 0.60-0.97; P = 0.028) population, respectively. In silico tools predicted that these loci altered function through via gene regulation.ConclusionWe identified several variants within the Wnt/beta-catenin pathway associated with MM susceptibility. Findings of this study highlight the potential genetic role of Wnt/beta-catenin signaling in MM etiology among a diverse patient population.

Dataset Information

Germline Genetic Variants in the Wnt/?-Catenin Pathway as Predictors of Colorectal Cancer Risk.

Publications

Germline Genetic Variants in the Wnt/β-Catenin Pathway as Predictors of Colorectal Cancer Risk.

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