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

• 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
• 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; 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

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.

项目摘要 多发性骨髓瘤（mm）是美国第二常见的血液系统恶性肿瘤，是 无法治愈的血浆细胞恶性肿瘤，标准化率通常高2至3倍 在非裔美国人（AA）中，与欧洲人（EA）相比。这种明显种族/种族的原因 差距在很大程度上不清楚。遗传敏感性，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的多余风险。特别是表观遗传修饰 胞嘧啶修饰，在MM的发展和发展中起关键作用。但是，与固体不同 肿瘤（例如，乳房，前列腺，结肠等），种族/族裔的明显表观遗传变化已经存在 显示出表观遗传学的肿瘤开始，进展和侵略性的差异 AA中MM多余风险的贡献没有很好地表征。表观遗传修饰的差异 是人类人群与复杂性状和疾病相关的内在特征。这 大多数以前的表观遗传学研究都使用了无法区分5--的技术 羟基环霉素（5HMC），生化稳定的表观遗传标记显示出明显的全基因组 来自研究经过精心修饰的细胞固醇（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了外周血淋巴细胞中的DNA作为 替代标本是因为从骨髓中获得CD138+肿瘤细胞在健康中抽吸 个人不可行。因此，我们建议阐明新型DNA修饰的影响， 特别是MM中种族/族裔差异的无细胞DNA（CFDNA）中的5HMC。循环cfDNA 片段通过循环死亡或增殖的癌细胞释放到血液中。因此，cfDNA 由隐藏在骨髓，骨髓微环境或外肺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和其他方面的相关性 血液学恶性肿瘤，包括CFDNA中的5HMC修饰与总体有关 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及其前体之间鉴定了涉及5HMC的人群特异性途径。我们的中心 假设是与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修改会导致AA的多余风险。我们将确定全基因组5HMC特征 对于CFDNA中的MM（AIM 1），并研究了CFDNA生成的骨髓肿瘤细胞和MM相关的5HMC和 微环境（目​​标2）。我们将阐明特定于人口的5HMC特征和EA之间的途径 和MM的AA患者（AIM 3）。该项目很重要，因为它提供了及时，全面的 识别新颖的表观遗传学因素及其差异的策略，这些差异将为新目标提供新的目标 该无法治愈的疾病的高风险人群中的个性化预防措施。