Abstract 5077: Common, germline genetic variants within the Wnt/beta-catenin stem cell pathway as determinants of multiple myeloma risk
Authors: Hildebrandt Michelle A. T. , Ye Yuanqing , Zhou Yeling , Orlowski Robert , Wu Xifeng 
Published: May 2015

Multiple Myeloma (MM) is the second most common hematologic malignancy in the US being diagnosed in over 20,500 individuals each year. The etiology of MM remains unclear and little is known regarding the effect of common, germline genetic variants on MM risk. Towards this, we investigated polymorphisms in the Wnt/beta-catenin signaling pathway as predictors of risk. This pathway is an essential regulator of hematopoietic and cancer stem cells and has been shown to be aberrantly activated in MM cells. A total of 171 variants were genotyped in 409 MM cases and 410 age, gender, and ethnicity-matched healthy controls. In the main effect analysis, 10 polymorphisms were significantly associated with risk, of which eight associations were supported by bootstrap analysis with over 80% of the re-samplings reaching P&lt;0.05. This includes rs7916830 in BTRC, the ubiquitin E3 ligase for the pathway, that was associated with a 28% reduction in risk (95% CI: 0.59-0.89, P=0.0017). This variant is located ∼2.7 kb upstream of BTRC and is predicted to alter a transcription factor binding site located within a region of high regulatory potential. The incidence of MM in African-Americans (AA) is twice that in Caucasian-American (CA) individuals. Therefore, we performed stratified analyses to identify cross-ethnic and ethnic-group specific associations. Twelve variants were associated with MM risk in the AA population, including five that remained consistent in the bootstrap analysis. The most significant finding was for FZD5:rs3731568 that resulted in a significant reduction in risk (OR: 0.42(0.23-0.78), P=0.0057). Interestingly, only three of these variants were also significantly associated with risk in the overall analysis with adjustment for ethnicity, and only one was also significant in the CA-only analysis (DKK1:rs1569199 - ORoverall: 0.67(0.49-0.90); ORaa: 0.50(0.28-0.91); ORca: 0.68(0.46-0.99)). One of these ethnic-group specific associations was FZD6:rs951826, resulting in a 2.12-fold increased risk in the AA population (95% CI: 1.04-4.33, P=0.040), yet suggestive opposite effects in the overall and CA populations (ORoverall: 0.74(0.39-1.40); ORca: 0.64(0.32-1.26)). Gene-based analyses confirmed these ethnic-group differences with no overlap at the gene level between the associations with MM risk for the CA and AA populations. Together, these findings provide additional support of the role of the Wnt/beta-catenin signaling pathway in MM, while also identifying global and ethnic-group specific genetic associations, particularly with regard to the AA population.

Citation Format: Michelle A. T. Hildebrandt, Yuanqing Ye, Yeling Zhou, Robert Orlowski, Xifeng Wu. Common, germline genetic variants within the Wnt/beta-catenin stem cell pathway as determinants of multiple myeloma risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5077. doi:10.1158/1538-7445.AM2014-5077