Mechanisms of loss of heterozygosity in cancer

描述（由申请人提供）：我们的目标是了解杂合性缺失（洛）的机制。洛缺失是由同源染色体间的信息传递引起的。洛缺失常发生于肿瘤中，但在正常细胞中很少出现。洛缺失事件可以改变DNA序列，跨越许多基因，通过改变基因活性和表达水平扰乱关键途径。因此，尽管洛缺失的发生频率远低于点突变，但洛缺失对肿瘤生物学有着深远的影响。洛依赖于同源性定向修复（HDR）途径，并且长期以来被认为仅依赖于作用于DNA双链断裂的HDR。然而，我们最近的研究结果挑战了这一观点。我们已经发现了HDR的替代途径，其在下调典型HDR时受到刺激，并支持信息从有切口的供体DNA转移到有切口的受体（Davis和Maizels，PNAS，出版中）。洛缺失的机制尚未明确，这限制了我们将这种致突变标记作为基因组不稳定性来源的能力。我们的研究旨在明确洛缺失的机制，并建立洛缺失在人类肿瘤中的激活机制。为此，我们提出以下两个具体目标：目标1。我们将定义进行洛的因素。目标二。我们将确定洛在人类癌细胞中是如何调节的。意义：靶向促进或调节洛的因子的治疗可能会减少洛频率，并减少危及许多治疗的肿瘤内异质性。相关性杂合性缺失（洛）在肿瘤中经常发生，它导致了促进癌症发展的驱动突变和阻碍治疗的肿瘤内异质性。我们的目标是了解洛缺失的机制。这将使得下调洛缺失频率和减少洛缺失对肿瘤发生的贡献成为可能。

DESCRIPTION (provided by applicant): Our goal is to understand the mechanisms of loss of heterozygosity (LOH). LOH results from transfer of information from one homologous chromosome to the other. LOH occurs frequently in tumors but is rarely evident in normal cells. LOH events can alter DNA sequence over many megabases, spanning many genes, perturbing critical pathways by altering gene activities and expression levels. Thus, even though LOH occurs much less frequently than point mutation, LOH contributes profoundly to tumor biology. LOH depends upon homology-directed repair (HDR) pathways, and it was long presumed to depend exclusively upon HDR acting at DNA DSBs. However our recent results challenge that view. We have discovered an alternative pathway of HDR, which is stimulated upon downregulation of canonical HDR and supports transfer of information from a nicked donor DNA to a nicked recipient (Davis and Maizels, PNAS, in press). The mechanisms of LOH have not been clearly defined, and this limits our ability to minimize this mutagenic signature as a source of genomic instability. We propose to define the mechanisms of LOH, and establish how LOH is activated in human tumors. To do this we propose the following two Specific Aims: Aim 1. We will define the factors that carry out LOH. Aim 2. We will determine how LOH is regulated in human cancer cells Significance: Therapies that target the factors that promote or regulate LOH may diminish LOH frequencies, and reduce the intratumor heterogeneity that compromises many therapies. Relevance Loss of heterozygosity (LOH) occurs frequently in tumors, where it contributes to driver mutations that promote development of cancer and intratumor heterogeneity that thwarts therapy. Our goal is to understand the mechanism of LOH. This will make it possible to downregulate LOH frequencies and diminish the contribution of LOH to tumorigenesis.