(PDQ5)Integrated Genetic and Epigenetic Prognostication for Acute Myeloid Leukemi

(PDQ5)急性髓性白血病的综合遗传和表观遗传预测

• 批准号: 8687082
• 负责人: MARTIN CARROLL
• 金额: $ 24.36万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687082
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Age; Biological Assay; CEBPA gene; Cancer Center; Cancer Diagnostics; Clinical; Collection; Cytogenetics; DNA Methylation; DNA Mutational Analysis; DNA Sequence; Data; Data Set; Development; Discrimination; Disease; Doctor of Medicine; Eastern Cooperative Oncology Group; Epigenetic Process; Evaluation; FLT3 gene; Gene Mutation; Genes; Genetic; Genetic Markers; Goals; Health; Hereditary Disease; High Dose Chemotherapy; Karyotype; Laboratories; Lead; Ligation; Mediating; Methodology; Methylation; Microspheres; Molecular; Molecular Genetics; Mutate; Mutation; Mutation Analysis; Myelogenous; NPM1 gene; Outcome; Patients; Refractory; Relapse; Reproducibility; Research; Risk; Risk Assessment; Sampling; Stratification; Survival Rate; System; Technology; Testing; Therapeutic; Work; base; chemotherapy; clinical practice; cohort; epigenetic marker; genetic analysis; genome wide methylation; genome-wide; improved; leukemia; molecular pathology; next generation; novel; outcome forecast; prognostic; response

DESCRIPTION (provided by applicant): Current risk stratification in acute myeloid leukemia (AML) is based on clinical variables such as age and traditional cytogenetics. Recently, molecular genetic analysis has proven to be useful in risk stratification and therapeutic management of AML patients. For example, FLT3, NPM1, and CEBPA mutational analysis was found to improve risk stratification in patients without karyotypic abnormalities. However, all current prognostication schema fail to robustly separate patients who will be cured by chemotherapy from those who will relapse. To address this problem, we have performed studies to enhance molecular prognostication using both genetic and epigenetic markers and, importantly, to make these assays clinically feasible. The Levine Laboratory recently completed mutational analysis of 16 genes mutated in AML in a large cohort of patients with de novo AML and identified novel predictors of outcome, including TET2, PHF6, DNMT3A, and IDH2 R140Q mutations. Importantly, combinations of these genetic variables provide enhanced prognostic ability for many AML patients, leading to predictions of survival of greater than 80% in these sub-groups. In other cases, combinations of genetic variables provide only modest discrimination of prognosis. Additionally, the Melnick laboratory has recently demonstrated through genome-wide DNA methylation analysis that response to therapy for AML patients can be predicted with a fifteen-gene DNA methylation panel. This panel was identified using a genome-wide methylation profiling platform not currently amenable to use in the clinical setting. Taken together, these studies lead to the hypothesis that AML is a disease characterized by both genetic and epigenetic changes and that optimal prognostication schema will need to incorporate both types of markers. To make the prognostic use of DNA methylation profiling feasible in clinical practice, we have developed a microsphere-based methylation profiling (MELP) assay which uses technology widely available in molecular pathology laboratories (see below for details). Initial evaluation demonstrates that the assay robustly reproduces results generated with the original HELP (HpaII tiny fragment enrichment by ligation-mediated PCR) research-based methylation platforms and predicts outcome in a previously described AML cohort (HOVON). In addition, we have implemented a next generation based DNA sequencing methodology to determine genetic mutations in AML and applied this methodology to a recently annotated UPENN AML group (described below). In this proposal, we will further develop a robust, clinically feasible, AML prognostication system combining genetic, epigenetic and clinical features. We will initially focus on confirming a robust DNA methylation based clinical assay and then integrate this assay into a multivariate risk assessment system being developed. The latter system should serve as a platform for ongoing development of a fully integrated prognostic system as we move towards realization of the goal of personalized cancer diagnostics.

描述（由申请人提供）：急性髓样白血病（AML）的当前风险分层基于临床变量，例如年龄和传统的细胞遗传学。最近，事实证明，分子遗传分析可用于AML患者的风险分层和治疗管理。例如，发现FLT3，NPM1和CEBPA突变分析可改善没有核型异常的患者的风险分层。但是，所有当前的预后模式都无法与将通过化学疗法治愈的患者与将复发的患者进行牢固地分离。为了解决这个问题，我们进行了研究，以使用遗传和表观遗传学标记来增强分子预后，并且重要的是使这些测定在临床上可行。莱文实验室最近完成了大量从头AML患者中AML突变的16个基因的突变分析，并确定了预后的新预测指标，包括TET2，PHF6，DNMT3A和IDH2 R140Q突变。重要的是，这些遗传变量的组合为许多AML患者提供了增强的预后能力，从而预测了这些亚组中80％以上的生存率。在其他情况下，遗传变量的组合仅提供对预后的适度歧视。此外，梅尔尼克实验室最近通过全基因组DNA甲基化分析证明了对AML患者治疗的反应可以通过15种基因DNA甲基化面板预测。使用目前不适合在临床环境中使用的全基因组甲基化谱图平台来识别该面板。综上所述，这些研究导致了以下假设：AML是一种以遗传和表观遗传学变化为特征的疾病，最佳预测模式将需要纳入两种类型的标记。为了使DNA甲基化分析在临床实践中可行，我们开发了一种基于微球的甲基化分析（MELP）测定法，该测定法使用了在分子病理实验室中广泛使用的技术（有关详细信息，请参见下文）。最初的评估表明，该测定可鲁棒地再现基于研究的甲基化平台所产生的原始帮助产生的结果（HPAII微小的片段富集），并在先前描述的AML队列（Hovon）中预测结果。此外，我们已经实施了下一代DNA测序方法，以确定AML中的基因突变，并将该方法应用于最近注释的UPENN AML组（如下所述）。在此提案中，我们将进一步开发一种结合了遗传，表观遗传和临床特征的强大，可行的AML预后系统。我们最初将着重于确认基于DNA甲基化的强大临床测定法，然后将该测定法整合到开发的多元风险评估系统中。后一个系统应作为持续开发完全集成的预后系统的平台，因为我们朝着实现个性化癌症诊断目标的目标。