Epigenomic markers of circulating cell-free DNA and treatment outcome in multiple myeloma

多发性骨髓瘤循环游离 DNA 的表观基因组标记和治疗结果

基本信息

批准号：
10204951
负责人：
BRIAN C-H CHIU
金额：
$ 63.5万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-06 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204951
关键词：
Biological Blood Blood Tests Bone Marrow Bone Marrow Cells Bone marrow biopsy Cells Chemicals Chromatin Clinical Clinical Management Cytogenetics Cytosine DNA DNA Markers DNA analysis Dependence Development Diagnosis Disease Drug resistance Epigenetic Process Evolution Foundations Gene Expression Gene Expression Profile Genes Genomic DNA Genomics Goals Hematologic Neoplasms Heterogeneity Human Genome Hypermethylation Image Individual Institution Investigation Knowledge Label Link Location Malignant Neoplasms Maps Mission Modeling Modification Molecular Monitor Multiple Myeloma Neoadjuvant Therapy Outcome Oxides Patients Performance Phase Phenotype Plasma Plasma Cells Population Process Prognosis Prognostic Marker Public Health Refractory Disease Regulator Genes Relapse Research Residual Neoplasm Role Sampling Sampling Biases Techniques Technology Testing Therapeutic Therapeutic Intervention Time Treatment Failure Treatment outcome United States National Institutes of Health base bone cell cell free DNA circulating biomarkers clinical risk demethylation epigenetic marker epigenome epigenomics high risk improved indexing minimally invasive mortality nano neoplastic cell next generation sequencing novel marker personalized management precision medicine predictive marker prognostic significance prospective relapse prediction resistance mechanism response seal transcriptome treatment response tumor tumor heterogeneity

项目摘要

PROJECT SUMMARY Multiple myeloma (MM) is a heterogeneous group of disorders with distinct bone marrow dependence, clinical features, prognosis, and response to therapy. Despite the best available treatments, MM is generally incurable and patients will eventually develop relapsed/refractory disease. Early relapse is associated with poor clinical outcomes and overall survival. There are currently no effective markers that can predict which patients will have early relapse. The long-term goal is to better understand the role of epigenetics in treatment outcomes of MM and develop a non-invasive, clinically convenient approach for predicting relapse. The overall objective of this application is to evaluate 5-hydroxymethylcytosines (5hmC) and 5-methylcytosines (5mC) in circulating cell-free DNA (cfDNA) from MM patients as markers for predicting patients at high risk of early relapse at the time of diagnosis. It is known that greater epigenetic heterogeneity is linked with poorer survival and relapse. We propose that sensitive and robust cfDNA-based epigenetic markers may offer greater convenience and minimal invasiveness for predicting early relapse in MM. In addition to 5mC, changes in 5hmC, an abundant and stable modified cytosine with a distinct gene regulatory function from 5mC, have been implicated in cancer development and pathobiology. However, due to technological constraints, previous studies of cancer epigenetics have largely interpreted modified cytosines as 5mC only, and no study has evaluated the distinct roles of 5hmC and 5mC in the therapeutic significance for MM. To fill the current research and technical gaps and consider the high impact of developing a minimally invasive blood test for MM, we will utilize a highly sensitive and robust technique developed by our team, the nano-Seal-Seq (a chemical labeling technique integrated with the next-generation sequencing), to accurately determine 5hmC and 5mC profiles in cfDNA and CD138+ myeloma “cancer” cells from bone marrow. The central hypothesis is that the 5hmC/5mC signatures in cfDNA at diagnosis can distinguish MM patients by early relapse status. In Aim 1, we will profile 5hmC and 5mC in cfDNA from ~240 MM patients (relapse within 12 months [early relapse, n=120] vs. >12 months [late relapse, n=120] of starting initial therapy) to develop an integrated predictive index for early relapse. We will validate the 5hmC/5mC markers in two independent replication population of ~750 MM patients. In Aim 2, we will profile 5hmC/5mC in 300 genomic DNA from CD138+ myeloma cells from patients with paired plasma cfDNA to determine a bone marrow-based predictive index, of which the performance will be compared with that of the cfDNA markers. In Aim 3, we will investigate change of 5hmC/5mC in serial cfDNA over time in 130 patients to characterize its therapeutic significance. The proposed research is highly significant, because it is expected to vertically advance understanding of the biological basis for early relapsed MM and promote the development of a new paradigm for epigenetic monitoring (and eventually, treatment) that has broad translational importance in the personalized management of high-risk patients.

项目概要多发性骨髓瘤 (MM) 是一组具有明显骨髓依赖性的异质性疾病，临床特征、预后和治疗反应尽管有最好的治疗方法，MM 通常是无法治愈的。患者最终会出现复发/难治性疾病，早期复发与临床表现不佳有关。目前没有有效的标志物可以预测哪些患者会发生这种情况。长期目标是更好地了解表观遗传学在治疗结果中的作用。 MM 并开发一种非侵入性、临床上方便的方法来预测复发。此应用用于评估循环中的 5-羟甲基胞嘧啶 (5hmC) 和 5-甲基胞嘧啶 (5mC) 来自 MM 患者的游离 DNA (cfDNA) 作为预测早期复发高风险患者的标记物众所周知，表观遗传异质性越大，生存率和复发率越低。我们认为，基于 cfDNA 的灵敏且稳健的表观遗传标记可能会提供更大的便利性和预测 MM 早期复发的微创性除了 5mC 之外，5hmC 的变化也很丰富。和稳定修饰的胞嘧啶具有与 5mC 不同的基因调节功能，与癌症有关然而，由于技术限制，以前对癌症的研究。表观遗传学在很大程度上将修饰的胞嘧啶解释为仅 5mC，并且没有研究评估不同的胞嘧啶 5hmC和5mC在MM治疗中的作用填补目前的研究和技术空白。并考虑到开发 MM 微创血液检测的巨大影响，我们将利用高度我们团队开发的灵敏且稳健的技术，nano-Seal-Seq（一种化学标记技术）与下一代测序集成），准确测定 cfDNA 和 5hmC 和 5mC 谱来自骨髓的 CD138+ 骨髓瘤“癌细胞” 核心假设是 5hmC/5mC 特征。诊断时的 cfDNA 可以通过早期复发状态区分 MM 患者。在目标 1 中，我们将分析 5hmC 和来自约 240 名 MM 患者的 cfDNA 中有 5mC（12 个月内复发 [早期复发，n=120] vs. > 12 个月 [晚期复发复发，n=120]开始初始治疗），以制定早期复发的综合预测指数。在目标 2 中，我们在约 750 名 MM 患者的两个独立复制群体中验证 5hmC/5mC 标记物。将分析来自配对血浆患者的 CD138+ 骨髓瘤细胞的 300 个基因组 DNA 中的 5hmC/5mC cfDNA 以确定基于骨髓的预测指数，其性能将与在目标 3 中，我们将研究 130 年内连续 cfDNA 中 5hmC/5mC 的变化。所提出的研究非常重要，因为它是预计将纵向推进对早期复发 MM 生物学基础的理解，并促进开发一种具有广泛应用前景的表观遗传监测（以及最终的治疗）新范式高危患者个性化管理的转化重要性。