Determining the Influence Genomic Instability During Embryogenesis has on Tumor Penetrance

摘要 携带杂合p53生殖系突变的Li Fraumeni患者， 到癌症这些个体的发病率可能差异很大;有些人患有肿瘤 在1岁之前发病，而一些个体在74岁之前不存在癌症。P53是 因此，了解影响肿瘤转移率的机制将对预测个体癌症风险有很大益处。已经 研究表明，野生型p53等位基因缺失（杂合性缺失（洛））的肿瘤与较早的肿瘤发病有关。这些洛缺失事件是基因组改变相关的结果。 基因组不稳定。因此，具有频繁基因组不稳定性事件的个体是 p53洛缺失的可能性更大，肿瘤发病更早。我们和其他人已经证明，染色体不稳定性事件已记录在非常早期的人类，小鼠和斑马鱼 胚胎这使我们产生了这样的假设，即个体之间胚胎发生过程中基因组不稳定性的差异决定了肿瘤的变异性，而基因组不稳定性的差异驱动了p53洛缺失。 LFS患者的生存率。虽然直观，但这一假设尚未得到正式验证。内 我们将通过定义在胚胎发生期间具有高基因组不稳定性和低基因组不稳定性的动物的群组来测试这一假设，并确定基因组不稳定性的量。 不稳定性决定了LFS动物模型中的肿瘤转移率。预期总体 所提出的工作的影响是，它将从根本上推进我们的理解如何 胚胎发生过程中的基因组不稳定性影响肿瘤发生。这将成为未来治疗干预和癌症风险预测生物标志物的基础。

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.