Alem A Belachew1, Xifeng Wu1, Rashida Callender1, Rosalie Waller2, Robert Z Orlowski3, Celine M Vachon4, Nicola J Camp2, Elad Ziv5, Michelle A T Hildebrandt6. 1. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States. 2. Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84108, United States. 3. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States. 4. Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55902, United States. 5. Department of Medicine, Division of General Internal Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA, 94143, United States. 6. Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, United States. Electronic address: mhildebr@mdanderson.org.
Abstract
BACKGROUND: Aberrant 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. METHODS: We 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. RESULTS: Seven 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. CONCLUSION: We 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.
BACKGROUND: Aberrant 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. METHODS: We 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. RESULTS: Seven 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. CONCLUSION: We 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.
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