Replication Profiling as a Diagnostic Tool in B-cell Acute Lymphoblastic Leukemia

描述（由申请人提供）：尽管成功鉴定了具有高或低治疗失败风险的急性淋巴细胞白血病（ALL）的不同亚型，但约三分之一的诊断缺乏任何预后特征，这些患者中有10-25%复发。因此，迫切需要新的诊断工具来改善这些患者的风险分层。我们提出了一个一流的评估复制时间的时间顺序复制的兆碱基大小的染色体片段作为一个预后癌症的生物标志物。异常的复制时间与许多癌症有着密切的联系，但还没有对其作为癌症生物标志物来源的潜力进行系统的评估。我们的长期目标是评估复制时机的潜力，以用于治疗以及改善临床结果。我们的近期目标是将复制定时程序的独特功能与缺乏强预后特征的ALL患者的结局联系起来。我们的中心假设是，复制时间的差异可以区分好与坏的结果在这个子集的患者。我们的初步数据表明，我们可以有效地分析在库冷冻患者样品中的全基因组复制定时，并且可以在不同来源的ALL之间鉴定复制定时的显著差异（“指纹”）。下一个关键步骤是确定这些差异是否可以为风险分层提供信息。我们的基本原理是，达到这一目标的最有效方法是分析一个定义的ALL患者队列，这些患者缺乏强有力的预后特征，以询问复制时间是否可以识别将遭受复发的患者。Aim 1将从60个具有已知结果但缺乏强预后特征的NCI高风险B细胞ALL样本库中收集全基因组复制时序数据。Aim 2将从Aim 1的结果中推导出复制定时指纹，并执行将这些指纹与临床数据相关联的统计分析 为了病人该提案意义重大，因为如果成功，该项目可以显著提高识别有复发风险的患者的能力，并引入一种全新的生物标志物类型。该方法是创新的，因为它代表了复制时间作为预后癌症生物标志物的一流评估。我们希望这些研究能够揭示复制时间指纹与患者结局相关的力量。作为R21，“高回报”是一种全新类型的生物标志物的潜力;“高风险”方面是我们尚未将复制时间指纹与患者结果联系起来。

DESCRIPTION (provided by applicant): Despite successes in identifying distinct subtypes of acute lymphocytic leukemia (ALL) with high or low risk of treatment failure, approximately one third of all diagnoses lack any prognostic features and 10-25% of these patients recur. Hence, there is a strong need for new diagnostic tools to improve risk stratification for these patients. We propose a first in class evaluation of replication timing-the temporal order of replication of megabase-sized chromosomal segments-as a prognostic cancer biomarker. Abnormal replication timing has been anecdotally associated with many cancers, but no systematic evaluation of its potential to serve as a source of cancer biomarkers has been performed. Our long-term goal is to evaluate the potential of replication timing to be exploited for therapy as wel as to improve clinical outcome. Our immediate goal is to link unique features of the replication-timing program to outcome for those ALL patients that lack strong prognostic features. Our central hypothesis is that replication-timing differences can distinguish between good vs. poor outcome within this subset of patients. Our preliminary data demonstrate that we can effectively analyze replication timing genome-wide in banked frozen patient samples, and that significant differences ("fingerprints") in replication timing can be identified between ALLs of different orign. The next critical step is to determine whether these differences can be informative for risk stratification. Our rationale is that the most effective way to reach this goal is to analyze a defined cohort of ALL patients that lack strong prognostic features to ask whether replication timing can identify patients that will suffer a recurrence. Aim1 will collect genome-wide replication timing data from 60 banked NCI high-risk B-cell ALL samples with known outcomes that lack strong prognostic features. Aim2 will derive replication-timing fingerprints from the results of Aim 1 and perform statistical analyses correlating these fingerprints with clinical data for the patients. The proposal is significant because, if successful, this project could dramaticaly improve the ability to identify patients at risk of relapse and introduce an entirely novel genre o biomarkers. The approach is innovative because it represents a first in class evaluation of replication timing as a prognostic cancer biomarker. We expect these studies to reveal the power of replication timing fingerprints to associate with patient outcome. As an R21, the "high payoff" is the potential for a whole new genre of biomarkers; the "high risk" aspect is that we have not yet linked replication-timing fingerprints to patient outcome.