Role of Disadvantage, Mutographs and T Cell Immunity on MGUS in African Americans

ABSTRACT The goal of this investigation is to characterize the influence of structural racism on associations of mutational signatures and T cell immunity on the excess risk of monoclonal gammopathy of undetermined significance (MGUS) observed in African American (AA) populations. MGUS is a necessary precursor to Multiple Myeloma (MM), which is the most common blood cancer affecting AA populations. Despite the increased incidence, 5-year survival is similar by African and European ancestry suggesting that underlying differences in driver events accumulated in early-stage precursor disease provide an evolutionary trajectory that predisposes AA populations to greater risk and subsequent mortality. Despite its importance, our current understanding of MGUS etiology is almost exclusively inferred from MM and from patients of European origin resulting in a gap in knowledge of underlying events driving the disparity. By directly evaluating MGUS, we will improve our understanding of the environmental and genomic mechanisms underlying early-stage precursor disease, and differences by ancestry. In this proposed investigation, we will test the overarching hypotheses that distinct mutational signatures and T cell immunity are associated with the presence of MGUS and that elements of structural racism modify the effect of mutational signatures and T cell immunity on the risk of MGUS, which accounts for the excess risk observed in AA populations. Our objective to model the influence of macro- and micro- environment factors relative to early genomic events underlying the evolutionary trajectory of MGUS is a critical step toward characterizing the biological differences driving the disparity of disease in AA populations and may provide a clinically impactful tool for early detection, clinical monitoring and advancing interception strategies. The specific aims are to (1) determine the influence of disadvantage on the excess risk of MGUS in AA populations, (2) identify mutographs and T cell immune responses associated with the excess MGUS risk in AA populations, and (3) determine the extent to which disadvantage modifies the effect of mutographs and T-cell immunity on the presence of MGUS. The proposal is highly innovative, timely and leverages existing resources and comprehensive, high-quality data and biospecimens systematically collected in well-characterized diverse populations to advance our understanding of MGUS etiology, and a biological basis for the excess risk observed in AA populations. Anticipated findings will uncover modifiable risk factors, identify vulnerable populations at-risk for MGUS-MM and may provide a foundation to discover novel therapeutic targets and effective interception strategies to improve the health of underserved and historically marginalized populations subjected to inequity, injustice, or exclusion.