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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.

摘要携带杂合性p53胚系突变的Li Fraumeni患者高度易感敬癌症。这些个体的外显率差异很大；一些个体患有肿瘤。发病年龄在1岁之前，而一些人在74岁之前没有出现癌症。P53是因此，了解影响肿瘤外显性的机制将对预测个体癌症风险有很大的帮助。一直以来野生型P53等位基因缺失(杂合性缺失(LOH))的肿瘤与较早发病相关。这些杂合性缺失事件是相关基因组改变的结果基因组的不稳定性。因此，频繁发生基因组不稳定事件的个体是更有可能发生P53杂合性缺失，肿瘤发病时间更早。我们和其他人已经证明，在非常早期的人类、老鼠和斑马鱼中已经记录了染色体不稳定事件。胚胎。这导致我们提出一个假设，即个体之间胚胎发育过程中基因组不稳定性的差异决定了肿瘤的变异性，这种差异导致了p53杂合性缺失。 LFS患者的外显率。虽然这是直觉的，但这一假设尚未得到正式检验。在在这个提议中，我们将通过定义在胚胎发育过程中具有高基因组不稳定性和低基因组不稳定性的动物队列来检验这一假说，并确定基因组数量在LFS动物模型中，不稳定性决定了肿瘤的穿透性。预期的总体情况拟议工作的影响是，它将从根本上促进我们对如何胚胎发生过程中基因组的不稳定性会影响肿瘤的发生。这将为未来的治疗干预和癌症风险的预测生物标志物奠定基础。