Genetic determinants of multiple myeloma risk within the Wnt/beta-catenin signaling pathway. (August 2021)

• Record Type: Journal Article
• Authors: Belachew, Alem A.; Wu, Xifeng; Callender, Rashida; Waller, Rosalie; Orlowski, Robert Z.; Vachon, Celine M.; Camp, Nicola J.; Ziv, Elad; Hildebrandt, Michelle A.T.
• Is Part Of: Cancer epidemiology. Volume 73(2021)
• Publication Date: 2021-08
• Subjects: Myeloma -- Wnt/beta-catenin -- Disparities -- Genetic variation -- Susceptibility; Cancer -- Epidemiology -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Diagnosis -- Periodicals; Carcinogenesis -- Periodicals; 616.994005
• DOI: 10.1016/j.canep.2021.101972
• Languages: English
• ISSNs: 1877-7821

Abstract

Highlights: Variants within the Wnt/beta-catenin pathway were associated with MM risk in a multi-ethnic population. Two LRP6 variants were protective for MM in non-Hispanic whites after internal replication and external validation. Polymorphisms in CSNK1D and BTRC were identified as susceptibility loci in non-Hispanic black and Hispanic populations. 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.