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: 8594233
• 负责人: David M Gilbert
• 金额: $ 9.57万
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594233
• 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）：尽管成功地识别出急性淋巴细胞性白血病（全）的明显亚型，患有高或低治疗衰竭的风险，但所有诊断中约有三分之一缺乏任何预后特征，并且这些患者中有10-25％复发。因此，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机的类评估 - 巨型Babase大小染色体段复制的时间顺序 - 作为预后癌症生物标志物。异常复制时机与许多癌症轶事相关，但是对其作为癌症生物标志物来源的潜力没有系统的评估。我们的长期目标是评估将复制时机利用进行治疗的潜力，以改善临床结果。我们的近期目标是将复制计划的独特功能链接起来，以使那些缺乏强大预后特征的患者的结果。我们的中心假设是，在这一子集中，复制差异可以区分良好与差的结果。我们的初步数据表明，我们可以有效地分析库存冷冻的患者样本中的复制正时基因组，并且可以在不同的Orign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提供风险分层的信息。我们的理由是，实现这一目标的最有效方法是分析所有缺乏强大预后特征的患者的确定队列，以询问复制时机是否可以识别会遭受复发的患者。 AIM1将从60个银行的NCI高风险B细胞中收集全基因组复制时间数据，所有样本都具有缺乏强大预后特征的已知结果。 AIM2将从AIM 1的结果中得出复制指纹，并进行统计分析，将这些指纹与临床数据相关联 对于患者。该提案很重要，因为，如果成功，该项目可以戏剧化提高鉴定有复发风险的患者并引入完全新颖的类型的生物标志物的能力。这种方法具有创新性，因为它代表了对复制时间作为预后癌症生物标志物的班级评估。我们预计这些研究能够揭示复制正时指纹与患者结局相关的功能。作为R21，“高收益”是一种新型生物标志物类型的潜力。 “高风险”方面是，我们尚未将指纹与患者结局联系起来。