权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel approach to whole genome methylation profiling of breast cancer

乳腺癌全基因组甲基化分析的新方法

基本信息

批准号：
8239536
负责人：
John R Edwards
金额：
$ 24.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2014-03-31
项目状态：
已结题

项目摘要

Understanding the role of methylation abnormalities undergone by cancer cell genomes is of great importance to cancer research and treatment; however, one major limitation has been the lack of a method for analyzing the methylation patterns of the entire genome simultaneously in a rapid, cost-effective manner. For instance, array based techniques cannot be used to reveal the methylation status of repetitive elements, which are hypothesized to play a key function in the altered expression patterns and rearrangements found in cancer cells. In particular, the role of methylation in breast cancer is still poorly understood; both hypermethylation of tumor suppressor gene promoters and global hypomethylation of the genome are thought to play significant early roles. The novel method presented here combines new techniques of fractionation of DNA according to methylation status and ultra-high throughput DMA sequencing using "Next- Gen" DMA sequencing technologies to allow efficient whole-genome methylation profiling even when only microgram amounts of DNA are available. We will use this technology to examine the complete genomic methylation status of a panel of breast cancer samples and study how these patterns correlate with various factors such as survival and recurrence to develop methylation profiles as a potentially powerful biomarker. We will use this data as a platform to elucidate the role methylation plays in breast cancer as a regulatory agent. We will determine if the hypomethylation that characterizes breast cancer is a stochastic or directed process and examine whether tumor suppressor hypermethylation is a key factor in breast cancer or if this is solely a sporadic event. We will also examine the effects of methylation on hotspots for chromosomal rearrangements, which are commonly found in breast cancer. This project, via a whole genome methylation profiling method that is unbiased and capable of investigating the methylation status of all sequences including the repeated sequences known to be demethylated in breast cancer, will provide a first look into the complete methylation landscape of breast cancer and provide new insights into epigenetic abnormalities in cancer.

了解癌细胞基因组发生甲基化异常的作用，癌症研究和治疗的重要性;然而，一个主要的限制是缺乏方法用于以快速、成本有效的方式同时分析整个基因组的甲基化模式。例如，基于阵列的技术不能用于揭示重复元件的甲基化状态，据推测，它们在改变的表达模式和重排中起着关键作用，在癌细胞中。特别是，甲基化在乳腺癌中的作用仍然知之甚少; 肿瘤抑制基因启动子的高甲基化和基因组的整体低甲基化是被认为扮演着重要的早期角色。这里提出的新方法结合了新技术，根据甲基化状态的DNA分级分离和使用“Next- Gen”DMA测序技术允许高效的全基因组甲基化分析，即使在只有可获得微克量的DNA。我们将利用这项技术来检查完整的基因组一组乳腺癌样本的甲基化状态，并研究这些模式如何与各种生存和复发等因素，以开发甲基化谱作为潜在的强大生物标志物。我们将利用这些数据作为一个平台，阐明甲基化在乳腺癌中的作用，作为一种调节基因，剂我们将确定乳腺癌的低甲基化特征是随机的还是定向的处理并检查肿瘤抑制基因超甲基化是否是乳腺癌的关键因素，只是偶发事件我们还将研究甲基化对染色体多态性热点的影响。重排，这在乳腺癌中常见。这个项目通过一个全基因组甲基化一种无偏的、能够研究所有序列甲基化状态的分析方法包括已知在乳腺癌中被去甲基化的重复序列，将提供对乳腺癌的完整甲基化景观，并为表观遗传异常提供新的见解在癌症中。