Grant Number:	5U01CA249955-04 Interpret this number
Primary Investigator:	Brown, Elizabeth
Organization:	University Of Alabama At Birmingham
Project Title:	Epigenetic Contribution to the Excess Risk of Mgus in African Americans
Fiscal Year:	2024

ABSTRACT 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.




ULK4 and CDKN2A polymorphisms influence the risk of developing monoclonal gammopathy of undetermined significance.
Authors: Sánchez-Maldonado J.M. , Macauda A. , Cabrera-Serrano A.J. , Thomsen H. , Güler M. , Horst R.T. , van Guelpen B. , Vodicka P. , Landi S. , Chattopadhyay S. , et al. .
Source: International Journal Of Cancer, 2026-03-11 00:00:00.0; , .
EPub date: 2026-03-11 00:00:00.0.
PMID: 41813586
Related Citations

Sex differences in the clinical presentation of patients with newly diagnosed multiple myeloma.
Authors: Ong K.L. , Arnold K.D. , Wessel M.C. , Ravi G. , Davies F.E. , Morgan G.J. , Brown E.E. .
Source: Cancer, 2026-01-15 00:00:00.0; 132(2), p. e70192.
PMID: 41521749
Related Citations

Multiple myeloma risk linked to DNA damage response genes.
Authors: Conry M. , Ostrovnaya I. , Kemel Y. , Sinha S. , Baughn L.B. , Avery B. , Maclachlan K. , Groner V. , Banaszak L. , Norman A. , et al. .
Source: Journal Of Hematology & Oncology, 2026-01-06 00:00:00.0; , .
EPub date: 2026-01-06 00:00:00.0.
PMID: 41495781
Related Citations

Influence of structural racism on cancer health disparities: Tailoring measures relevant to multiple myeloma.
Authors: Roland H.B. , McGuire C.M. , Baskin M.L. , Esposito M.H. , Baker E. , Brown E.E. .
Source: Cancer, 2024-08-11 00:00:00.0; , .
EPub date: 2024-08-11 00:00:00.0.
PMID: 39127894
Related Citations

Anthropometric traits and risk of multiple myeloma: differences by race, sex and diagnostic clinical features.
Authors: Arnold K.D. , Ong K.L. , Ravi G. , Cutshall H. , Purnell K. , Wessel M.C. , Godby K.N. , Bal S. , Giri S. , Rogers L.Q. , et al. .
Source: British Journal Of Cancer, 2024-06-07 00:00:00.0; , .
EPub date: 2024-06-07 00:00:00.0.
PMID: 38849476
Related Citations

Identification of novel genetic loci for risk of multiple myeloma by functional annotation.
Authors: Macauda A. , Briem K. , Clay-Gilmour A. , Cozen W. , Försti A. , Giaccherini M. , Corradi C. , Sainz J. , Niazi Y. , Ter Horst R. , et al. .
Source: Leukemia, 2023-09-18 00:00:00.0; , .
EPub date: 2023-09-18 00:00:00.0.
PMID: 37723249
Related Citations

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.
Authors: Clavero E. , Sanchez-Maldonado J.M. , Macauda A. , Ter Horst R. , Sampaio-Marques B. , Jurczyszyn A. , Clay-Gilmour A. , Stein A. , Hildebrandt M.A.T. , Weinhold N. , et al. .
Source: International Journal Of Molecular Sciences, 2023-05-09 00:00:00.0; 24(10), .
EPub date: 2023-05-09 00:00:00.0.
PMID: 37239846
Related Citations