Elucidating novel epigenetic modifications implicated in multiple myeloma risk disparities

项目摘要 多发性骨髓瘤（MM）是美国第二常见的血液恶性肿瘤，是一种多发性骨髓瘤。 无法治愈的浆细胞恶性肿瘤，标准化发病率通常高出2至3倍 非洲裔美国人（AA）与欧洲裔美国人（EA）相比。这一明显的种族/族裔原因 差距在很大程度上仍不清楚。遗传易感性、社会经济因素和肥胖是重要的风险因素 MM的因素，但它们不能完全解释AA中MM的过度风险。表观遗传修饰，特别是 胞嘧啶修饰在MM的发展和进展中起关键作用。 肿瘤（例如，乳腺、前列腺、结肠等）种族/民族群体中明显的表观遗传变化 表观遗传学研究表明，肿瘤的发生、发展和侵袭性存在差异， 对AA中MM的过度风险的贡献还没有很好的表征。表观遗传修饰的差异 是人类群体之间的内在特征，与复杂的特征和疾病有关。的 大多数以前的表观遗传学研究使用的技术不能区分5- 羟甲基胞嘧啶（5 hmC），一个生化稳定的表观遗传标记，表现出明显的全基因组 来自充分研究的修饰胞嘧啶，5-甲基胞嘧啶（5 mC）的分布和调节作用。在 此外，表观遗传流行病学研究主要使用来自外周血淋巴细胞的DNA， 替代标本，因为从健康受试者的骨髓抽吸物中获得CD 138+肿瘤细胞， 个人是不可行的。因此，我们建议阐明新的DNA修饰的影响， 特别是循环无细胞DNA（cfDNA）中的5 hmC对MM中种族/民族差异的影响。 碎片通过循环死亡或增殖的癌细胞释放到血流中。因此，cfDNA 由隐藏在骨髓中的肿瘤细胞、骨髓微环境或髓外疾病产生 可以在血浆中检测到。我们已经证明了cfDNA衍生的5 hmC在MM和其他疾病中的相关性。 血液恶性肿瘤，包括cfDNA中特异性5 hmC修饰，与总体 MM的生存率;不同的5 hmC特征反映了淋巴瘤亚型之间的分子差异;以及 在MM及其前体之间鉴定了涉及5 hmC的群体特异性途径。我们的中央 假设cfDNA中与MM相关的特异性5 hmC特征反映了原发性肿瘤细胞， 特定的5 hmC修饰导致AA的过度风险。我们将识别全基因组5 hmC签名 在cfDNA中检测MM（目的1），并在cfDNA配对的骨髓肿瘤细胞中研究MM相关的5 hmC， 微环境（目标2）。我们将阐明群体特异性5 hmC签名和EA之间的途径， 和AA伴MM患者（Aim 3）。这个项目是重要的，因为它提供了一个及时和全面的 确定MM的新表观遗传贡献者及其差异的策略， 针对这种不治之症的高危人群采取个性化预防干预措施。

PROJECT SUMMARY Multiple myeloma (MM), the second most common hematologic malignancy in the United States, is an incurable plasma cell malignancy with standardized incidence rates that are typically 2- to 3-times higher among African Americans (AA) compared to European Americans (EA). Reasons for this apparent racial/ethnic disparity remain largely unclear. Genetic susceptibility, socioeconomic factors, and obesity are important risk factors for MM, but they do not fully explain the excess risk of MM in AA. Epigenetic modifications, particularly cytosine modifications, play a critical role in the development and progression of MM. However, unlike solid tumors (e.g., breast, prostate, colon, etc.) where distinct epigenetic changes in racial/ethnic groups have been shown to account for the differences in tumor initiation, progression, and aggressiveness, the epigenetic contributions to the excess risk of MM in AA are not well characterized. Differences in epigenetic modifications are an intrinsic feature between human populations and associated with complex traits and diseases. The majority of previous epigenetic studies have used technologies that cannot distinguish 5- hydroxymethylcytosines (5hmC), a biochemically stable epigenetic mark showed distinct genome-wide distributions and regulatory roles from the well-studied modified cytosines, 5-methylcytosines (5mC). In addition, epigenetic epidemiology studies have predominantly used DNA from peripheral blood lymphocytes as surrogate specimens because obtaining CD138+ tumor cells from the bone marrow aspirates in healthy individuals is not feasible. Therefore, we propose to elucidate the influence of novel DNA modifications, specifically the 5hmC in circulating cell-free DNA (cfDNA) on racial/ethnic disparities in MM. Circulating cfDNA fragments are released into the bloodstream by circulating dead or proliferating cancerous cells. Thus, cfDNA produced by tumor cells hiding in the bone marrow, bone marrow microenvironment, or extramedullary disease can be detected in plasma. We have demonstrated the relevance of cfDNA-derived 5hmC in MM and other hematological malignancies, including that specific 5hmC modifications in cfDNA were associated with overall survival of MM; distinct 5hmC signatures reflected molecular differences between subtypes of lymphoma; and population-specific pathways involving 5hmC were identified between MM and its precursors. Our central hypotheses are that specific 5hmC signatures associated with MM in cfDNA reflect primary tumor cells, and specific 5hmC modifications contribute to the excess risk in AA. We will identify genome-wide 5hmC signatures for MM in cfDNA (Aim 1) and investigate MM-associated 5hmC in cfDNA-paired bone marrow tumor cells and microenvironment (Aim 2). We will elucidate population-specific 5hmC signatures and pathways between EA and AA patients with MM (Aim 3). This project is significant because it offers a timely and comprehensive strategy to identify novel epigenetic contributors to MM and its disparities that will provide new targets for individualized preventive interventions in high-risk populations for this incurable disease.