Epigenetic contribution to the excess risk of MGUS in African Americans

摘要 这项研究的目的是表征DNA甲基组对增加的风险的影响。 在非裔美国人中观察到的未确定意义的单克隆性伽马病(MGUS)与 欧洲裔美国人。为了促进对表观遗传修饰的更好理解， RACE观察到的MGUS风险的不同趋势，我们将解决MMDPQ1：哪些风险因素，单独或在 合作，解释未确定意义的单克隆性伽马病(MGUS)发病率的变化 在不同的种族之间？MGUS先于多发性骨髓瘤(MM)，后者是最常见的血癌 影响非裔美国人，特征是细胞对凋亡的抵抗导致延长存活和 克隆扩增的、细胞遗传学异质性的、产生抗体的肿瘤细胞在骨骼中的聚集 骨髓和髓外部位。与非裔美国人相比，非裔美国人患MGUS的风险高出2到3倍 欧洲裔美国人和一些公认的危险因素(种族、男性、肥胖、家族史 淋巴系恶性肿瘤)对观察到的MGUS风险差异知之甚少。不过，有证据表明 生殖系成分，DNA序列的遗传改变本身并不能解释这种差异。最新进展 表观基因组学为表征基因活性或种系可塑性的可遗传变化提供了新的机会 过去环境暴露造成的差异，这可以显著提高我们对MGUS的理解 病因学、血统差异，并为改进高危人群的临床监测提供了新的见解。 我们将测试最重要的假设，即不同的甲基组特征与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。使用表观基因组的方法，我们将利用一个独特的机会来探索 在DNA中的差异甲基化位置，从一个特征良好的治疗天真的网络中获得 在利用最新技术和分析进展的同时，对MGU和MM的种群进行分析。这个项目 利用现有的合作伙伴关系、资源以及全面、高质量的临床数据和生物样本 系统地收集在一个具有良好特征的治疗天真人群网络中，以改善我们的 了解种族观察到的MGUS风险的不同趋势，并推进所需的一套生物标志物 加强对高危非裔美国人MGUS临床病程的预测和管理。

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.