DNA methylation as a diagnostic marker in AML

描述(申请人提供)：启动子中的DNA甲基化异常 基因区域在多种人类癌症中被发现，并被认为是 与基因沉默有关。限制性里程碑基因组扫描(RLGS)是 目前唯一允许扫描数千个启动子的技术 人类癌症中异常DNA甲基化的序列。异常DNA 甲基化最近被证明是一个主要的贡献者和早期事件 肿瘤发生，尤其是在急性髓系白血病(AML)的发展过程中。 在这个应用中，我们建议研究DNA甲基化在 急性髓细胞白血病，特别强调临床相关性。将使用的样本 因为这项研究将来自CALGB白血病组织库。我们的假设是 表观遗传变化(DNA甲基化)与遗传一样重要 白血病发生的改变，但其程度被低估了。自.以来 甲基化变化可能会影响基因的转录很可能是 这些表观遗传差异导致了潜在的分子缺陷。 核型正常的急性髓系白血病。随后，可以使用异常甲基化的靶标 目的：确定急性髓细胞白血病新的诊断或预后生物标志物。为了测试这一点 假设我们的具体目标是(1)研究一个子集的甲基化情况 核型正常的急性髓系白血病，原始细胞计数为50%。(2)严谨统计 生物信息学分析将识别特定的诊断和复发 甲基化事件、预测甲基化事件的候选子类以及 最后，与病程等临床数据相关的甲基化目标 完全缓解的可能性。(3)高信息量甲基化的一小部分 目标将通过亚硫酸氢盐排序进行详细研究。MS-PCR检测将是 开发了允许对更大的患者样本进行筛查的技术。统计 将执行分析以确定甲基化事件的值作为 诊断生物标志物或作为具有预测价值的标志物。

DESCRIPTION (Provided by applicant): Aberrant DNA methylation in the promoter region of genes is found in a variety of human cancers and is thought to be associated with gene silencing. Restriction Landmark Genomic Scanning (RLGS) is currently the only technique that allows the scanning of thousands of promoter sequences for aberrant DNA methylation in human cancer. Aberrant DNA methylation was recently shown to be a major contributor and an early event in tumorigenesis, especially in the development of acute myeloid leukemia (AML). In this application we propose to investigate the role of DNA methylation in AML with special emphasis on clinical correlates. The samples that will be used for this study will come from the CALGB Leukemia Tissue Bank. Our hypothesis is that epigenetic changes (DNA methylation) are equally important as genetic alterations in leukemogenesis but have been underestimated in its extend. Since methylation changes could affect the transcription of genes it is likely that these epigenetic differences contribute to the molecular defects that underlie normal karyotype AML. Subsequently, aberrantly methylated targets can be used to identify novel diagnostic or prognostic biomarkers in AML. To test this hypothesis our specific aims are (1) to study methylation profiles in a subset of normal karyotype AML with blast counts >50 percent. (2) Rigorous statistical and bioinformatical analysis will identify diagnosis and relapse specific methylation events, candidate subclass predicting methylation events and finally methylation targets that correlate with clinical data such as duration of complete remission. (3) A small subset of highly informative methylation targets will be studied in detail by bisulfite sequencing. MS-PCR tests will be developed that allow (4) screening of larger patient samples. Statistical analysis will be performed to determine the value of a methylation event as a diagnostic biomarker or as a marker with predictive value.