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 African Americans compared to
European Americans. To facilitate an improved understanding of the epigenetic modifications underlying the
disparate trends in MGUS risk observed by race, we will address MMDPQ1: What risk factors, singularly or in
cooperation, explain the variation in monoclonal gammopathy of undetermined significance (MGUS) incidence
among different races? MGUS precedes Multiple Myeloma (MM), which is the most common blood cancer
affecting African Americans, 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. Risk of MGUS is 2- to 3-fold higher among African Americans compared to
European Americans and beyond a few well-established risk factors (race, male sex, obesity, family history of
lymphoid malignancy) little is known about the observed disparity in MGUS risk. Although, evidence suggests a
germline component, inherited alterations in DNA sequence alone does not explain the disparity. Advances in
epigenomics offer new opportunities to characterize the heritable changes in gene activity, or plasticity in germline
variation due to past environmental exposures, which could significantly improve our understanding MGUS
etiology, differences by ancestry 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
observed in African Americans and that aberrant epigenetic modification influences the disparity in risk 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 the disparate trends in MGUS risk observed by race and to advance a set of biomarkers required
to improve efforts to predict and manage MGUS clinical course in high-risk African American populations.
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