Epigenomic determinants of clinical outcomes in MCL patients treated on E1405

描述（由申请人提供）：套细胞淋巴瘤（MCL）是一种侵袭性非霍奇金淋巴瘤，其发病机制尚不清楚。大多数患者复发并最终死于这种疾病，迫切需要复发MCL的新治疗方案。来自我们实验室和其他实验室的数据表明，MCL基因组中DNA甲基化的分布发生了深刻的变化。受甲基化变化影响的基因涉及关键的细胞内过程，如转录，细胞周期和细胞存活。全基因组甲基化和表达的整合分析可以产生生物学见解，并识别仅通过基因表达不明显的患者亚组。此外，使用基于阵列的技术的甲基化特征可以对患者结果进行预后和预测。通过大规模平行测序（MPS）测量DNA甲基化和RNA转录本丰度具有更大的动态范围，更灵敏，并且比基于微阵列的方法更完整地捕获基因组信息。我们假设，DNA甲基化和基因表达的整合高分辨率分析可以确定原发性MCL临床结局的关键表观基因组决定因素。因此，我们建议使用RNA-seq和HELP标记的深度测序来测定来自三个MCL患者队列的治疗前肿瘤样品中的全基因组RNA表达和甲基化。一项VcR-CVAD联合利妥昔单抗维持治疗MCL的多中心II期临床试验（B）由威斯康星州大学网络治疗的MCL患者和（c）MCL患者在Hackensack大学医学中心接受治疗。我们将鉴定与预后相关的差异甲基化/表达基因，然后建立一个预测临床结果的多变量模型。我们的相关研究利用这些高分辨率平台和库存标本提供的独特机会，以（1）改善可能从化疗中获益最多的MCL患者的选择（2）识别仅通过基因表达谱不明显的临床相关患者亚组和（3）了解MCL异质性临床结局的生物学基础。

DESCRIPTION (provided by applicant): Mantle cell lymphoma (MCL) is an aggressive form of Non-Hodgkin's lymphoma whose pathogenesis is not clearly understood. Most patients relapse and eventually die of this disease, and new treatment options for relapsed MCL are urgently needed. Data from our lab and others suggests that there are profound changes in distribution of DNA methylation across the MCL genome. The genes affected by changes in methylation involve critical intracellular processes like transcription, cell cycle and cell survival. Integratve analysis of genome-wide methylation and expression can yield biological insights and identify patient subgroups that are not apparent by gene expression alone. Moreover, methylation signatures using array-based techniques can be prognostic and predictive for patient outcomes. Measurement of DNA methylation and RNA transcript abundance by massively parallel sequencing (MPS) has a greater dynamic range, is more sensitive, and captures genomic information more completely than microarray based approaches. We hypothesize that integrative high-resolution analysis of DNA methylation and gene expression can identify the key epigenomic determinants of clinical outcomes in primary MCL. We therefore propose to use RNA-seq and HELP-tagged deep sequencing to assay genome-wide RNA expression and methylation, in pretreatment tumor samples from three cohorts of MCL patients (a) Patients treated on ECOG 1405, a multicenter Phase II clinical trial of VcR-CVAD with maintenance Rituximab for MCL (b) MCL patients treated by the University of Wisconsin Network and (c) MCL patients treated at Hackensack University Medical Center. We will identify the differentially methylated/expressed genes associated with prognosis and then build a multi-variable model predictive for clinical outcomes. Our correlative studies leverage the unique opportunity provided by these high resolution platforms and banked specimens towards (1) improving selection of MCL patients likely to benefit most from chemotherapy (2) identifying clinically relevant patient sub-groups not apparent by gene expression profiling alone and (3) understanding the biological basis for heterogeneous clinical outcomes in MCL.