Using epigenomic subtyping to understand the racial differences in lymphoma

使用表观基因组亚型来了解淋巴瘤的种族差异

• 批准号: 9455051
• 负责人: BRIAN C-H CHIU
• 金额: $ 25.43万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9455051
• 关键词: Address; Adult; Affect; African; African American; Aftercare; Age; American; B-Lymphocytes; Biological; Biological Assay; Biological Markers; Biological Process; Breast; Cell physiology; Chicago; Clinical; Colon; Cytosine; DNA Methylation; Data; Development; Diagnosis; Disease; Endometrium; Enhancers; Environmental Risk Factor; Epigenetic Process; Ethnic Origin; Ethnic group; European; Exploratory/Developmental Grant; Gene Expression; Genes; Health Services Accessibility; Heterogeneity; Human; Incidence; Individual; Link; Liver; Lymphoma; Machine Learning; Malignant Neoplasms; Modification; Molecular; Outcome; Pathogenesis; Pathologic; Patients; Population; Prevention approach; Preventive Intervention; Prostate; Protocols documentation; Race; Regulator Genes; Regulatory Element; Relapse; Research; Risk; Sampling; Scanning; Solid Neoplasm; Specificity; Techniques; Tetanus Helper Peptide; Therapeutic Intervention; Time; Tissues; Treatment outcome; Tumor Tissue; Universities; Work; base; biobank; bisulfite sequencing; clinically significant; cost efficient; disparity reduction; epigenetic marker; epigenetic variation; epigenome; epigenomics; ethnic difference; health disparity; improved; indexing; innovation; large cell Diffuse non-Hodgkin' s lymphoma; member; mortality; novel; novel strategies; public health relevance; racial and ethnic; racial difference; social; stressor; survival outcome; treatment response; tumor; tumor initiation

PROJECT SUMMARY Diffuse large B-cell lymphoma (DLBCL), the most common aggressive type of lymphomas, is characterized by marked clinical and pathological heterogeneity that is reflected at the molecular level. It is well known that although the incidence rates for DLBCL were lower for African Americans (AA) than for European Americans (EA), AA patients were diagnosed at a significantly younger age and have worse 5-year survival compared with EA patients. The reason for this apparent racial/ethnic difference is unclear and cannot be fully explained by social stressors or access to care. We speculate that epigenetic variations could underlie the racial/ethnic differences because the pathogenesis of DLBCL is strongly linked to perturbation of epigenetic mechanisms, and population-specific cytosine modifications are a fundamental feature between human populations. In addition, greater epigenetic heterogeneity is linked with more aggressive DLBCL and poorer survival outcomes. Most prior studies of DLBCL epigenetics have assessed 5-methylcytosines (5mC) in predominantly EA patients. No studies have evaluated 5-hydroxymethylcytosines (5hmC), an emerging stable and abundant modification with distinct gene regulatory and cellular functions, due mainly to technical limitations. Most importantly, no studies have assessed concurrently 5mC and 5hmC in both EA and AA DLBCL patients. Without an effective technique to obtain the complete landscape of modified cytosines, development of targeted epigenetic approaches to improve DLBCL disparities is unlikely. The objective of this Exploratory/Developmental study is to distinguish 5hmC from 5mC at the time of DLBCL diagnosis between AA and EA patients and evaluate their clinical significance. Our hypothesis is that the 5mC/5hmC signatures in tumor tissues differ between AA and EA patients and that these differences contribute to the well-known racial/ethnic differences in DLBCL risk and outcomes. The Specific Aims are to 1) distinguish 5hmC from 5mC in EA and AA patients and evaluate population-specific 5mC/5hmC loci; and 2) determine therapeutic response-associated 5hmC/5mC loci. Specifically, we will obtain tissues for 120 patients with DLBCL (60 AA and 60 EA) from the University of Chicago Lymphoma Biobank. We will combine an innovative technique, the Tet-assisted Bisulfite Sequencing (TAB-Seq) and the new Illumina EPIC array to accurately distinguish 5hmC from 5mC. We will perform an epigenome-wide scan to assess differences in 5hmC/5mC modification levels between AA and EA patients at presentation and also integrate both modifications to predict therapeutic response, defined as relapse within 24 months after treatment. This proposal addresses a critical research question in a highly innovative, cost-efficient, and timely manner, providing important data for the first time on the complete landscape of modified cytosines for racial/ethnic differences in DLBCL. The results are expected to have positive impact because it is possible that the identified epigenetic loci/biomarkers will provide new targets for individualized preventive and therapeutic interventions to decrease mortality and burden of DLBCL.

项目概要 弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的侵袭性淋巴瘤类型，其特点是 显着的临床和病理异质性反映在分子水平上。众所周知， 尽管非洲裔美国人 (AA) 的 DLBCL 发病率低于欧洲裔美国人 (EA)，与 AA 患者相比，AA 患者的诊断年龄明显更年轻，并且 5 年生存率更差 与 EA 患者。这种明显的种族/民族差异的原因尚不清楚，也无法完全解释 受到社会压力或获得护理的机会。我们推测表观遗传变异可能是种族/民族差异的基础 差异是因为 DLBCL 的发病机制与表观遗传机制的扰动密切相关， 群体特异性胞嘧啶修饰是人类群体之间的基本特征。在 此外，更大的表观遗传异质性与更具侵袭性的 DLBCL 和较差的生存率相关 结果。大多数先前的 DLBCL 表观遗传学研究主要评估了 5-甲基胞嘧啶 (5mC) 电针患者。尚无研究评估 5-羟甲基胞嘧啶 (5hmC)，这是一种新兴的稳定且丰富的 主要由于技术限制，具有不同的基因调控和细胞功能的修饰。最多 重要的是，尚无研究同时评估 EA 和 AA DLBCL 患者的 5mC 和 5hmC。 如果没有有效的技术来获得修饰胞嘧啶的完整景观，开发 采用有针对性的表观遗传学方法来改善 DLBCL 差异的可能性不大。此举的目的 探索性/发展性研究的目的是在 DLBCL 诊断时区分 5hmC 和 5mC AA和EA患者并评估其临床意义。我们的假设是 5mC/5hmC 特征 AA 和 EA 患者的肿瘤组织中存在差异，这些差异导致了众所周知的 DLBCL 风险和结果的种族/民族差异。具体目标是 1) 将 5hmC 与 EA 和 AA 患者中的 5mC 并评估人群特异性 5mC/5hmC 位点； 2) 确定治疗方法 反应相关的 5hmC/5mC 位点。具体来说，我们将获取 120 名 DLBCL 患者的组织（60 AA 和 60 EA）来自芝加哥大学淋巴瘤生物库。我们将结合创新技术， Tet 辅助亚硫酸氢盐测序 (TAB-Seq) 和新型 Illumina EPIC 阵列可准确区分 5hmC 从 5mC 起。我们将进行全表观基因组扫描以评估 5hmC/5mC 修饰水平的差异 AA 和 EA 患者在就诊时进行比较，并整合这两种修改来预测治疗 缓解，定义为治疗后 24 个月内复发。该提案涉及一项关键研究 以高度创新、具有成本效益且及时的方式提出问题，首次提供重要数据 DLBCL 中种族/民族差异的修饰胞嘧啶的完整景观。结果是预期的 产生积极影响，因为确定的表观遗传位点/生物标志物可能会提供新的 个体化预防和治疗干预措施的目标，以降低 DLBCL 的死亡率和负担。