Mechanisms of loss of heterozygosity in cancer

描述(由申请者提供)：我们的目标是了解杂合性缺失(LOH)的机制。LOH是由一条同源染色体向另一条同源染色体传递信息所致。LOH在肿瘤中经常发生，但在正常细胞中很少见。LOH事件可以改变许多百万碱基上的DNA序列，跨越许多基因，通过改变基因活动和表达水平来扰乱关键途径。因此，尽管杂合性缺失发生的频率比点突变要少得多，但杂合性缺失对肿瘤生物学有深远的贡献。LOH依赖于同源定向修复(HDR)途径，长期以来一直被认为完全依赖于HDR在DNA DSB中的作用。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的另一种途径，它在规范的HDR下调时被刺激，并支持信息从NICK的供体DNA传输到NICK的接受者(Davis和Maizels，PNAS，在印刷中)。LOH的机制尚未明确，这限制了我们将这种突变特征作为基因组不稳定来源的能力降至最低的能力。我们建议定义杂合性缺失的机制，并确定杂合性缺失是如何在人类肿瘤中激活的。为此，我们提出了以下两个具体目标：目标1。我们将定义实施LOH的因素。目的2.我们将确定杂合性缺失在人类癌细胞中的调控意义：针对促进或调节杂合性缺失的因素的治疗可能会减少杂合性缺失的频率，并降低肿瘤内的异质性，这是许多治疗方法的妥协。相关性杂合性缺失(LOH)在肿瘤中经常发生，它导致驱动突变促进癌症的发展，并导致肿瘤内的异质性阻碍治疗。我们的目标是了解LOH的发病机制。这将可能下调LOH频率，减少LOH在肿瘤发生中的作用。

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.