Using epigenomic subtyping to understand the racial differences in lymphoma

项目总结 弥漫性大B细胞淋巴瘤(DLBCL)是最常见的侵袭性淋巴瘤，其特点是 明显的临床和病理异质性，反映在分子水平上。众所周知， 尽管非裔美国人(AA)的DLBCL发病率低于欧洲裔美国人 (EA)，再生障碍性贫血患者被诊断的年龄要小得多，与之相比，他们的5年生存率更低 对于电针患者。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的影响。我们推测表观遗传变异可能是种族/民族的基础。 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， 而群体特异性胞嘧啶修饰是人类群体之间的一个基本特征。在……里面 此外，表观遗传异质性越大，DLBCL侵袭性越强，存活率越低。 结果。大多数先前对DLBCL表观遗传学的研究都评估了5-甲基胞嘧啶(5mC)在主要 电针患者。还没有研究评估5-羟甲基胞嘧啶(5HmC)，它是一种新出现的稳定和丰富的 主要由于技术限制，具有不同的基因调节和细胞功能的修饰。多数 重要的是，还没有研究同时评估EA和AA DLBCL患者的5mC和5hmC。 如果没有一种有效的技术来获得修饰胞嘧啶的完整图景， 采用有针对性的表观遗传学方法来改善DLBCL的差异是不可能的。这样做的目的是 探索性/发育性研究是在诊断DLBCL时区分5hmC和5mC AA和EA患者，并评价其临床意义。我们的假设是5mC/5hmC签名 在肿瘤组织中AA和EA患者之间的差异，这些差异有助于众所周知 DLBCL风险和预后的种族/民族差异。具体目标是：1)将5hmC与 EA和AA患者的5mC，并评估人群特有的5mC/5hmC基因座；以及2)确定治疗 反应相关的5hmC/5mC基因座。具体地说，我们将获得120名DLBCL患者的组织(60AA 和60EA)来自芝加哥大学Lymphoma Biobank。我们将结合一项创新的技术， TET辅助亚硫酸盐测序(TAB-SEQ)和新的Illumina EPIC阵列精确区分5hmC 从5mC起。我们将进行表观基因组扫描，以评估5hmC/5mC修饰水平的差异 AA和EA患者之间的差异，并结合这两种修改来预测疗效 有效，定义为治疗后24个月内复发。这项建议涉及一项重要的研究 以高度创新、经济高效和及时的方式提问，首次提供重要数据 DLBCL中修饰胞嘧啶的种族/民族差异的完整图景。结果在意料之中 产生积极影响，因为已识别的表观遗传基因座/生物标记物可能会提供新的 个体化预防和治疗干预的目标，以降低DLBCL的死亡率和负担。

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.