Mechanisms of loss of heterozygosity in cancer

癌症杂合性丢失的机制

基本信息

批准号：
8805324
负责人：
Nancy Maizels
金额：
$ 16.8万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-19 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8805324
关键词：
Acquired uniparental disomy Alleles Base Pairing Biological Assay Bloom Syndrome Cancer cell line Chromosome Arm Chromosomes Complex Critical Pathways DNA DNA Damage DNA Repair DNA Sequence Development Disease Progression Down-Regulation Drug Targeting Event Exposure to Frequencies Genes Genetic Recombination Genets Genome Genomic Instability Goals Heterogeneity Human Loss of Heterozygosity Malignant Neoplasms Mammalian Cell Mediating Mutation Myeloproliferative disease Normal Cell Nucleotides PTEN gene Pathogenesis Pathway interactions Plasmids Play Point Mutation Proto-Oncogene Proteins c-akt Reporter Research Resolution Risk Role Sequence Homologs Sister Chromatid Small Interfering RNA Source Testing Tumor Biology Tumor Suppressor Proteins Uniparental Disomy Variant cancer cell cancer therapy cell killing cell type drug discovery ds-DNA genome-wide analysis helicase human FRAP1 protein interest mutant public health relevance repaired targeted treatment trend triple-negative invasive breast carcinoma tumor tumorigenesis

项目摘要

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.

描述（由申请人提供）：我们的目标是了解杂合性丢失（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 在肿瘤中频繁发生，但在正常细胞中很少出现。 LOH 事件可以改变许多兆碱基上的 DNA 序列，跨越许多基因，通过改变基因活性和表达水平来扰乱关键途径。因此，尽管 LOH 发生的频率远低于点突变，但 LOH 对肿瘤生物学做出了深远的贡献。 LOH 依赖于同源定向修复 (HDR) 途径，长期以来人们认为它完全依赖于 HDR 对 DNA DSB 的作用。然而，我们最近的结果挑战了这一观点。我们发现了 HDR 的另一种途径，该途径在规范 HDR 下调时受到刺激，并支持信息从带切口的供体 DNA 转移到带切口的受体（Davis 和 Maizels，PNAS，出版中）。 LOH 的机制尚未明确定义，这限制了我们最大限度地减少这种基因组不稳定来源的诱变特征的能力。我们建议定义 LOH 的机制，并确定 LOH 在人类肿瘤中是如何被激活的。为此，我们提出以下两个具体目标：目标 1. 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受到调节的意义：针对促进或调节 LOH 的因子的治疗可能会降低 LOH 频率，并减少影响许多治疗的肿瘤内异质性。相关性杂合性丢失 (LOH) 经常发生在肿瘤中，它会导致驱动突变，从而促进癌症的发展，并导致肿瘤内异质性阻碍治疗。我们的目标是了解 LOH 的机制。这将使得下调 LOH 频率并减少 LOH 对肿瘤发生的贡献成为可能。