Epigenetic contribution to the excess risk of MGUS in African Americans

摘要 这项研究的目的是描述DNA甲基化对增加的癌症风险的影响。 在非裔美国人中观察到的意义不明的单克隆丙种球蛋白病（MGUS）与 欧洲裔美国人。为了促进对表观遗传修饰的更好理解， 不同种族的MGUS风险的不同趋势，我们将解决MMDPQ 1：什么风险因素，单独或 合作，解释意义不明的单克隆丙种球蛋白病（MGUS）发病率的变化 在不同的种族？MGUS先于多发性骨髓瘤（MM），多发性骨髓瘤是最常见的血癌 影响非洲裔美国人，其特征在于细胞对凋亡的抵抗，导致生存期延长， 骨中克隆扩增的、细胞遗传学异质的、产生抗体的肿瘤细胞的积聚 骨髓和髓外部位。非裔美国人患MGUS的风险是非裔美国人的2- 3倍， 欧洲裔美国人和其他一些公认的风险因素（种族、男性、肥胖、家族病史） 淋巴系统恶性肿瘤）中所观察到的MGUS风险差异知之甚少。不过，有证据表明 生殖细胞成分，DNA序列的遗传改变本身并不能解释这种差异。进展 表观基因组学提供了新的机会，以表征基因活性的遗传变化，或生殖系的可塑性 由于过去的环境暴露，这可能会显着提高我们对MGUS的理解 病因学、祖先差异，并为改善高危人群的临床监测提供新的见解。 我们将检验一个总体假设，即不同的甲基化特征与MGUS的过度风险相关。 在非裔美国人中观察到，异常的表观遗传修饰通过改变 靶基因表达。使用表观基因组方法，我们将利用一个独特的机会， DNA中的差异甲基化位置从一个网络获得的良好表征，治疗初治 MGUS和MM群体，同时利用最新的技术和分析进展。这个项目 利用现有的合作伙伴关系、资源和全面、高质量的临床数据和生物标本 在一个充分表征的初治人群网络中系统收集，以改善我们的 了解按种族观察到的MGUS风险的不同趋势，并提出一套所需的生物标志物 改善预测和管理高危非裔美国人人群MGUS临床过程的努力。

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.