Entwicklung von Oligonukleotid-Arrays für die Charakterisierung von genomischen DNA-Methylierungsmustern in Tumoren

基因组DNA甲基化模式的变化是肿瘤发生的最早和最一致的特征之一。然而，人们对这些变化的性质及其在细胞转化中的作用知之甚少。由于缺乏基因组表观遗传分析的方法，该领域的进展受到阻碍。使用慢性淋巴细胞白血病作为模型系统，我们以前已经表明，异常的DNA甲基化谱可以作为一个有价值的标志物，用于临床肿瘤的特点。在独立实验中，我们建立了一种检测寡核苷酸微阵列上单碱基多态性的方法。由于一个定义的核苷酸的甲基化状态也可以解释为代表一个单核苷酸多态性，我们建议利用后者的技术进行全基因组，基因特异性分析的DNA甲基化模式。这种方法将导致基因组甲基化模式的详细表征。这些数据将与可用的临床数据和转录谱分析结果一起进行评价。我们的研究结果将使我们对DNA甲基化在肿瘤发生过程中的作用有一个基本的了解，并将为肿瘤的表观遗传分类提供基础。

Changes in genomic DNA methylation patterns are one of the earliest and most consistent features of tumourigenesis. However, very little is known about the nature of these changes and their role in cellular transformation. Progress in the field has been hampered by the unavailability of methods for genomic epigenetic profiling. Using chronic lymphocytic leukemia as a model system, we have shown previously that aberrant DNA methylation profiles can be used as a valuable marker for clinical tumour characterisation. In independent experiments, we have established a method for the detection of single-base polymorphisms on oligonucleotide microarrays. Because the methylation status of a defined nucleotide can also be interpreted to represent a single nucleotide polymorphism, we propose to utilise the latter technology for a genome-wide, gene-specific analysis of DNA methylation patterns. This approach will result in a detailed characterisation of genomic methylation patterns. The data will be evaluated together with the available clinical data and results from trancriptional profiling. Our results will allow fundamental insights into the role of DNA methylation during tumouresis and will provide the foundation for an epigenetic classification of tumours.