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

复制分析作为 B 细胞急性淋巴细胞白血病的诊断工具

• 批准号: 8445645
• 负责人: David M Gilbert
• 金额: $ 24.51万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-07 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445645
• 关键词: ABL1 gene; Acute Lymphocytic Leukemia; Algorithms; B-Cell Acute Lymphoblastic Leukemia; Biological; Biological Markers; Cancer Patient; Cells; Clinical; Clinical Data; Cytogenetics; DNA; DNA Sequence Rearrangement; Data; Defect; Diagnosis; Diagnostic; Disease; Disease remission; Evaluation; Fingerprint; Fingers; Freezing; Future; Genetic; Genomics; Goals; Laboratories; Link; Malignant Neoplasms; Mission; Outcome; Patients; Pattern; Printing; Prognostic Marker; Public Health; Recurrence; Relapse; Research; Risk; Risk Factors; Sampling; Source; Stratification; Time; Treatment Failure; Treatment Protocols; Trisomy 4; Work; cancer type; cohort; early experience; genome-wide; high risk; improved; innovation; leukemia; novel; novel diagnostics; outcome forecast; prognostic; programs; public health relevance; success; t(12; 21)(p13; q22); tool

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.

描述（由申请人提供）：尽管成功识别出具有高或低治疗失败风险的急性淋巴细胞白血病 (ALL) 不同亚型，但大约三分之一的诊断缺乏任何预后特征，并且这些患者中有 10-25% 会复发。因此，迫切需要新的诊断工具来改善这些患者的风险分层。我们提出了对复制时间（兆碱基大小的染色体片段复制的时间顺序）作为预后癌症生物标志物的一流评估。据传，异常复制时间与许多癌症有关，但尚未对其作为癌症生物标志物来源的潜力进行系统评估。我们的长期目标是评估复制时机用于治疗以及改善临床结果的潜力。我们的近期目标是将复制计时程序的独特特征与那些缺乏强预后特征的所有患者的结果联系起来。我们的中心假设是，复制时间差异可以区分这部分患者的良好结果和不良结果。我们的初步数据表明，我们可以有效地分析储存的冷冻患者样本中全基因组的复制时间，并且可以在不同来源的 ALL 之间识别复制时间的显着差异（“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。我们的理由是，实现这一目标的最有效方法是分析一组缺乏强预后特征的明确的 ALL 患者，以询问复制时机是否可以识别将遭受复发的患者。 Aim1 将从 60 个储存的 NCI 高风险 B 细胞 ALL 样本中收集全基因组复制计时数据，这些样本的结果已知，但缺乏强有力的预后特征。 Aim2 将从 Aim 1 的结果中得出复制时间指纹，并执行将这些指纹与临床数据相关联的统计分析 为了患者。该提案意义重大，因为如果成功，该项目可以极大地提高识别有复发风险的患者的能力，并引入全新的生物标志物类型。该方法具有创新性，因为它代表了对作为预后癌症生物标志物的复制时间的一流评估。我们期望这些研究能够揭示复制计时指纹与患者结果相关的力量。作为 R21，“高回报”是一种全新类型的生物标记物的潜力； “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。