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（LOH）的机制。LOH是信息从一条同源染色体转移到另一条同源染色体的结果。LOH经常发生在肿瘤中，但在正常细胞中很少明显。LOH事件可以改变许多兆碱基的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LOH的发生频率远低于点突变，但LOH对肿瘤生物学有着深远的贡献。LOH依赖于同源定向修复（homology-directed repair， HDR）途径，长期以来人们一直认为它完全依赖于作用于DNA dsb的HDR。然而，我们最近的结果挑战了这种观点。我们已经发现了HDR的另一种途径，该途径在规范HDR下调时受到刺激，并支持信息从缺口的供体DNA转移到缺口的受体（Davis和Maizels， PNAS, in press）。LOH的机制尚未明确定义，这限制了我们将这种诱变特征作为基因组不稳定来源最小化的能力。我们建议明确LOH的作用机制，并确定LOH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：我们将定义执行LOH的因素。目标2。我们将确定LOH在人类癌细胞中是如何被调节的。意义：针对促进或调节LOH的因素的治疗可能会减少LOH的频率，并减少肿瘤内的异质性，而这种异质性会损害许多治疗方法。相关性杂合性缺失（LOH）在肿瘤中经常发生，它会导致驱动突变，促进癌症的发展和阻碍治疗的肿瘤内异质性。我们的目标是了解LOH的机制。这将使下调LOH频率和减少LOH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.