Epigenetic contribution to the excess risk of MGUS in African Americans

The goal of this investigation is to characterize the influence of the DNA methylome central to the increased risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) observed in high-risk populations. MGUS precedes Multiple Myeloma (MM), which is characterized by cellular resistance to apoptosis leading to prolonged survival and accumulation of clonally expanded, cytogenetically heterogeneous, antibody producing tumor cells in the bone marrow and extramedullary sites. Beyond a few well-established risk factors, the etiology of MGUS/MM remains largely unknown. Although evidence suggests a germline component, inherited alterations in DNA sequence alone does not explain the risk. Advances in epigenomics offer new opportunities to characterize the heritable changes in gene activity, or plasticity in germline variation due to past exposures, which could significantly improve our understanding MGUS/MM etiology and provide new insight for improved clinical monitoring in high-risk populations. We will test the overarching hypothesis that distinct methylome signatures correlate with the excess risk of MGUS in high-risk populations by altering target gene expression. Using an epigenome-wide approach, we will capitalize on a unique opportunity to explore differentially methylated positions in DNA obtained from a network of well-characterized, treatment naïve populations of MGUS and MM while taking advantage of recent technological and analytic advances. This project leverages existing partnerships, resources and comprehensive, high-quality clinical data and biospecimens systematically collected in a well-characterized network of treatment-naïve populations, to improve our understanding of MGUS-MM etiology and to advance a set of biomarkers required to improve efforts to predict and manage MGUS-MM clinical course in high-risk populations.