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

• 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
• 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

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.

项目摘要 多发性骨髓瘤（MM）是一组异质性疾病，具有独特的骨髓依赖性，临床 特征，预后和对治疗的反应。尽管有最好的治疗方法，但MM通常是无法治愈的 患者最终会发展为中继/难治性疾病。早期继电器与临床不良有关 结果和整体生存。目前没有有效的标记可以预测哪些患者将 早日解脱。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并开发一种无创，临床方便的方法来预测继电器。总体目标 该应用是在循环中评估5-羟基甲苯（5HMC）和5-甲基环肽（5MC） 来自MM患者的无细胞DNA（CFDNA）是预测患者早期释放高风险的标志物 诊断时间。众所周知，更大的表观遗传异质性与较差的生存和救济有关。 我们建议基于CFDNA的敏感且强大的表观遗传标记可能会提供更大的便利性和 预测MM早期缓解的最小侵入性。除5MC外，5HMC的变化是绝对的 在癌症中隐含了具有不同基因调节功能的稳定改性的胞嘧啶，具有不同的基因调节功能 发展和病理学。但是，由于技术限制，先前对癌症的研究 表观遗传学在很大程度上将修饰的细胞氨解释为5MC，没有研究评估了独特的 5HMC和5MC在MM的治疗意义中的作用。填补当前的研究和技术空白 并考虑为MM开发微创血液测试的高影响，我们将使用高度 由我们的团队纳米式式播种（一种化学标签技术）开发的敏感和强大的技术 与下一代测序集成），以准确确定CFDNA和5MC的剖面 CD138+骨髓的骨髓瘤“癌”细胞。中心假设是5HMC/5MC签名 在CFDNA中，诊断可以通过早期继电器状态区分MM患者。在AIM 1中，我们将介绍5HMC和 cfDNA中的5MC来自约240毫米患者（12个月内复发[早期救济，n = 120] vs.>> 12个月[晚 复发，n = 120]开始初始疗法），以开发综合预测指数以提早缓解。我们将 在两个独立的复制人群中验证5HMC/5MC标记，约750毫米。在AIM 2中，我们 WILL来自CD138+骨髓瘤细胞的30​​0个基因组DNA中的5HMC/5MC来自配对等离子体患者的骨髓瘤细胞 CFDNA确定基于骨髓的预测指数，将其与该指数进行比较 cfDNA标记。在AIM 3中，我们将调查随时间推移的串行CFDNA的5HMC/5MC的变化130 患者表征其治疗意义。拟议的研究非常重要，因为它是 期望垂直提高对早期接力MM生物学基础的理解，并促进 开发具有广泛的表观遗传监测（有时是治疗）的新范式 在高风险患者的个性化管理中，翻译重要性。