Retrotransposon instability in glioblastoma multiforme

描述（由申请人提供）：侵袭性脑癌是当今诊断出的最具破坏性的恶性肿瘤之一。基础科学研究人员已经表明，在脑癌发展的复杂过程中，有许多步骤。这些包括我们细胞中移动的DNA序列的潜在激活，尽管以前没有人有研究这些DNA的方法。适当的DNA功能是细胞如何工作的核心，DNA的改变（突变）伴随着癌症的发展。我们提出，被称为转座子的移动的DNA序列在脑癌中被激活，然后反过来突变其他DNA序列。通过这种方式，移动的DNA可能有助于脑癌发展的开始或有效的早期治疗后疾病的继续发展。我们开发了一种新技术（通过深度测序或TIP-seq进行转座子插入位点分析），使我们能够定位人类细胞中最活跃的移动的DNA。我们建议应用TIP-seq在100个不同的多形性胶质母细胞瘤肿瘤病理样本中对全基因组范围内的移动的DNA进行分析。这将证明移动的DNA在人类脑癌中是否不稳定，以及它们是否会导致促进癌症生物学的突变。该项目将是第一个解决移动的DNA在人类癌症中的作用的项目之一，并可能使我们对许多癌症类型的工作机制大开眼界。

DESCRIPTION (provided by applicant): Aggressive brain cancers are among the most devastating of malignancies diagnosed today. Basic science researchers have shown that during the complex process of brain cancer development, there are many steps. These include the potential activation of mobile DNA sequences in our cells, though no one has had a means of studying these DNAs previously. Appropriate DNA function is at the heart of how a cell works and alterations in DNA (mutations) accompany cancer development. We propose that mobile DNA sequences known as transposons are activated in brain cancer and then in turn mutate other DNA sequences. In this way, mobile DNAs may contribute to the beginning of brain cancer development or the continued growth of disease after effective early therapy. We have developed a new technology (transposon insertion site profiling by deep sequencing or TIP-seq) that allows us to locate the most active mobile DNAs in human cells. We propose to apply TIP-seq to profile mobile DNAs genome-wide in 100 different pathologic samples from glioblastoma multiforme tumors. This should demonstrate whether mobile DNAs are unstable in human brain cancers and if they cause mutations that promote cancer biology. The project would be among the very first to address roles of mobile DNAs in human cancers, and will potentially open our eyes to mechanisms at work in many cancer types.