Retrotransposon instability in glioblastoma multiforme

描述(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DNA序列的潜在激活，尽管之前还没有人有办法研究这些DNA。适当的DNA功能是细胞工作的核心，DNA(突变)的变化伴随着癌症的发展。我们认为，被称为转座子的可移动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DNA可能有助于脑癌发展的开始，或在有效的早期治疗后疾病的持续增长。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)，使我们能够在人类细胞中定位最活跃的移动DNA。我们建议应用TIP-SEQ在100个不同的多形性胶质母细胞瘤的病理样本中分析全基因组的可移动DNA。这应该证明移动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。该项目将是第一批解决移动DNA在人类癌症中的作用的项目之一，并可能让我们看到许多癌症类型的作用机制。 与公共卫生相关：我们的大部分DNA来自被称为转座子或移动DNA的自我传播序列。技术障碍已经严重削弱了我们研究人类癌症这些序列的能力，尽管我的实验室已经取得了进展，现在打开了这种可能性。将重点放在脑癌上，这项拟议的努力应该会为我们对人类癌症遗传学的看法增加一个新的维度，最终影响我们如何理解和治疗这些疾病。

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. PUBLIC HEALTH RELEVANCE: Much of our DNA is derived from self-propagating sequences termed transposons or mobile DNAs. Technical impediments have severely curtailed our ability to study these sequences in human cancers, though my laboratory has made an advance that now opens this possibility. Focusing on brain cancers, the proposed effort should add a new dimension to our view of human cancer genetics, ultimately impacting how we understand and treat these diseases.