Elucidating novel epigenetic modifications implicated in multiple myeloma risk disparities

阐明与多发性骨髓瘤风险差异相关的新型表观遗传修饰

基本信息

批准号：
10912191
负责人：
BRIAN C-H CHIU
金额：
$ 30万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-22 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10912191
关键词：
Address Affect African American population Age American Biochemical Biology Blood Circulation Bone Marrow Bone Marrow Aspiration Bone Marrow Neoplasms Breast Cancer Detection Cancerous Cell Fraction Cells Chromosome abnormality Colon Complex Cytosine DNA DNA Modification Process Data Set Development Diagnosis Disease Disparity Dissection Endothelial Cells Enhancers Epigenetic Process Ethnic Population Etiology European Evaluation Extramedullary Genes Genetic Genetic Predisposition to Disease Genomics Genotype Goals Hematologic Neoplasms Human Incidence Individual Investigation Knowledge Lymphoma Malignant Neoplasms Malignant lymphoid neoplasm Mendelian randomization Modification Molecular Multiple Myeloma Mutation Obesity Pathway interactions Patients Peripheral Blood Lymphocyte Plasma Plasma Cells Play Population Primary Neoplasm Proliferating Prostate Research Resources Risk Risk Factors Role Sampling Socioeconomic Factors Solid Neoplasm Source Specimen Standardization Techniques Technology Tissues Tumor-Derived United States Work bone cell cell free DNA cell type epidemiology study epigenetic marker epigenomics ethnic difference ethnic disparity genome wide association study genome-wide genome-wide analysis high risk high risk population improved individualized prevention innovation neoplastic cell non-genetic novel novel strategies preventive intervention prognostication promoter racial difference racial disparity racial population recruit seal sex trait tumor initiation tumor microenvironment tumorigenesis

项目摘要

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.

项目概要多发性骨髓瘤 (MM) 是美国第二大常见的血液恶性肿瘤，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) 之间的差异。造成这种明显种族/民族的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 MM的因素，但它们并不能完全解释AA中MM的超额风险。表观遗传修饰，特别是胞嘧啶修饰在 MM 的发生和进展中发挥着关键作用。但与固体不同的是种族/族裔群体中存在明显表观遗传变化的肿瘤（例如乳腺癌、前列腺癌、结肠癌等）表观遗传学被证明可以解释肿瘤发生、进展和侵袭性的差异 MM 对 AA 中超额风险的贡献尚未得到很好的描述。表观遗传修饰的差异是人类群体之间的固有特征，与复杂的特征和疾病相关。这大多数先前的表观遗传学研究使用的技术无法区分 5- 羟甲基胞嘧啶 (5hmC)，一种生化稳定的表观遗传标记，在全基因组范围内表现出独特的特征来自经过充分研究的修饰胞嘧啶 5-甲基胞嘧啶 (5mC) 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外周血淋巴细胞的DNA作为替代样本，因为从健康人的骨髓中抽取 CD138+ 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，特别是循环游离 DNA (cfDNA) 中的 5hmC 对 MM 种族/民族差异的影响。循环cfDNA 通过循环死亡或增殖的癌细胞，碎片被释放到血流中。因此，cfDNA 由隐藏在骨髓、骨髓微环境或髓外疾病中的肿瘤细胞产生可以在血浆中检测到。我们已经证明了 cfDNA 衍生的 5hmC 在 MM 和其他疾病中的相关性血液恶性肿瘤，包括 cfDNA 中的特定 5hmC 修饰与总体 MM的生存；不同的 5hmC 特征反映了淋巴瘤亚型之间的分子差异；和在 MM 及其前体之间确定了涉及 5hmC 的人群特异性途径。我们的中央假设 cfDNA 中与 MM 相关的特定 5hmC 特征反映了原发性肿瘤细胞，并且特定的 5hmC 修饰会导致 AA 的过度风险。我们将鉴定全基因组 5hmC 特征用于 cfDNA 中的 MM（目标 1）并研究 cfDNA 配对的骨髓肿瘤细胞中与 MM 相关的 5hmC，以及微环境（目标 2）。我们将阐明人群特异性 5hmC 特征和 EA 之间的通路患有 MM 的 AA 患者（目标 3）。该项目意义重大，因为它提供了及时、全面的信息确定 MM 的新表观遗传因素及其差异的策略，这将为针对这种不治之症的高危人群采取个性化的预防干预措施。