Determining the Influence Genomic Instability During Embryogenesis has on Tumor Penetrance

确定胚胎发生过程中基因组不稳定性对肿瘤外显率的影响

基本信息

批准号：
9378133
负责人：
John M Parant
金额：
$ 19.38万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-11 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9378133
关键词：
5 year old Adult Age Age-Years Alleles Animal Model Animals Biological Models Cancer Model Cancer-Predisposing Gene Cells Chromosomal Instability Cohort Analysis DNA Sequence Alteration Diagnostic Disease Early Diagnosis Embryo Embryonic Development Event Fertilization Foundations Frequencies Future General Population Genes Genetic Genomic Instability Germ-Line Mutation Goals Human Image Inbred BALB C Mice Incidence Individual Inherited Intuition Knockout Mice Knowledge Lead Li-Fraumeni Syndrome Loss of Heterozygosity Malignant Neoplasms Modeling Molecular Mosaicism Mus Mutate Patients Penetrance Population Predisposition Prevalence Rare Diseases Risk Risk Factors Scanning Siblings Study models Sunburn Survival Analysis TP53 gene Techniques Testing Therapeutic Intervention Time Translating Tumor Suppressor Genes Variant Work Zebrafish cancer risk cohort design early onset experience in vivo melanoma mouse model mutant novel novel therapeutics predictive marker response sarcoma tumor tumorigenesis

项目摘要

Abstract Li Fraumeni patients, which harbor heterozygous p53 germ line mutation, are highly predisposed to cancers. The penetrance of these individuals can vary greatly; some individuals have tumor onset prior to age 1, while some individual that do not present with cancer by age 74. P53 is the most widely mutated gene in sporadic cancers, therefore understanding the mechanisms that impact tumor penetrance will have great benefit to predicting individual cancer risk. It has been demonstrated that tumor that loss the wild-type p53 allele (loss of heterozygosity (LOH)) associate with earlier tumor onset. These LOH event are the result of genomic alterations associated with genomic instability. Therefore, an individual with frequent genomic instability events is more likely to have p53 LOH, and earlier tumor onset. We and others have shown that chromosome instability events have been documented in very early stage humans, mouse and zebrafish embryos. This has lead us to develop the hypothesize that differences in genomic instability during embryogenesis between individuals, which drive p53 LOH, determine the variability in tumor penetrance of LFS patients. While intuitive this hypothesis has not been formally tested. Within this proposal we will test this hypothesis by defining cohorts of animals with high genomic instability and low genomic instability during embryogenesis and determine if the amount of genomic instability determined the tumor penetrance in an animal model of LFS. The expected overall impact of the proposed work is that it will fundamentally advance our understanding of a how genomic instability during embryogenesis impacts tumorigenesis. This will serve as the foundation for future therapeutic intervention and predictive biomarkers of cancer risk.

抽象的 Li Fraumeni患者具有杂合p53种生殖系突变的患者，是高度倾向的癌症。这些人的渗透可能会有很大的不同。有些人有肿瘤在1岁之前发病，而某些人在74岁时不患癌症的人。p53是零星癌中最广泛的突变基因，因此了解影响肿瘤渗透的机制将在预测个体癌症风险方面具有很大的好处。它一直证明损失野生型p53等位基因（杂合性丧失（LOH））的肿瘤与早期肿瘤发作有关。这些LOH事件是与基因组改变相关的结果与基因组不稳定性。因此，具有频繁基因组不稳定性事件的个体是更有可能患有P53 LOH，并且更早发作。我们和其他人表明，染色体不稳定性事件已在很早的人类，鼠标和斑马鱼中记录胚胎。这使我们发展了一个假设的，即个体之间的胚胎发生过程中基因组不稳定性的差异（驱动p53 loh）确定肿瘤的变异性 LFS患者的外观。虽然直观尚未正式检验该假设。之内该提案将通过定义胚胎发生过程中具有较高基因组不稳定性和低基因组不稳定性的动物的同类来检验这一假设，并确定基因组的量是否是否不稳定性确定了LFS动物模型中的肿瘤渗透性。总体预期拟议工作的影响是，它将从根本上提高我们对如何的理解胚胎发生过程中的基因组不稳定性会影响肿瘤发生。这将成为未来治疗干预和癌症风险的预测生物标志物的基础。