Genetic determinants of multiple myeloma risk within the Wnt/beta-catenin signaling pathway.

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 LRP6rs7966410 (OR 0.57; 95 % CI 0.38-0.88; P = 9.90 × 10-3) and LRP6rs7956971 (OR 0.64; 95 % CI 0.44-0.95; P = 0.027) remained significant in the internal and external populations. CSNK1Drs9901910 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). BTRCrs7916830 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.