Using epigenomic subtyping to understand the racial differences in lymphoma

项目摘要 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的侵袭性淋巴瘤类型，其特征在于： 在分子水平上反映的显著的临床和病理异质性。众所周知的是 尽管非裔美国人（AA）的DLBCL发病率低于欧洲裔美国人 (EA)AA患者被诊断出的年龄明显更小， 与患者。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。 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 由于DLBCL的发病机制与表观遗传机制的干扰密切相关， 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和更差的生存率相关 结果。大多数先前的DLBCL表观遗传学研究已经评估了5-甲基胞嘧啶（5 mC）在DLBCL中的主要作用。 患者。没有研究评估5-羟甲基胞嘧啶（5 hmC），一种新兴的稳定和丰富的 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 重要的是，没有研究同时评估EA和AA DLBCL患者中的5 mC和5 hmC。 如果没有有效的技术来获得修饰的胞嘧啶的完整景观， 改善DLBCL差异的靶向表观遗传方法是不可能的。的目的 探索性/开发性研究是为了在诊断DLBCL时区分5 hmC和5 mC， 分析AA和EA患者的临床意义。我们的假设是5 mC/5 hmC信号 AA和EA患者之间的肿瘤组织中的差异，这些差异有助于众所周知的 DLBCL风险和结局的种族/民族差异。具体目的是：1）区分5 hmC和 5 mC在EA和AA患者和评估群体特异性5 mC/5 hmC基因座;和2）确定治疗 反应相关的5 hmC/5 mC位点。具体而言，我们将获得120例DLBCL患者的组织（60例AA 和60 EA），来自芝加哥大学淋巴瘤生物库。我们将结合联合收割机的创新技术， Tet-assisted Bisulfite Sequencing（TAB-Seq）和新的Illumina EPIC阵列可准确区分5 hmC 5mC。我们将进行表观基因组扫描，以评估5 hmC/5 mC修饰水平的差异。 AA和EA患者之间的表现，并整合两种修改，以预测治疗 缓解定义为治疗后24个月内复发。该提案涉及一项关键的研究 以高度创新、具有成本效益和及时的方式提出问题，首次提供有关 修饰胞嘧啶用于DLBCL种族/民族差异的完整景观。结果预计 具有积极的影响，因为鉴定的表观遗传基因座/生物标志物可能会提供新的 个体化预防和治疗干预的目标，以降低死亡率和DLBCL的负担。

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.