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:
- 金额:$ 19.38万
- 依托单位:
- 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:
- 关键词:5 year oldAdultAgeAge-YearsAllelesAnimal ModelAnimalsBiological ModelsCancer ModelCancer-Predisposing GeneCellsChromosomal InstabilityCohort AnalysisDNA Sequence AlterationDiagnosticDiseaseEarly DiagnosisEmbryoEmbryonic DevelopmentEventFertilizationFoundationsFrequenciesFutureGeneral PopulationGenesGeneticGenomic InstabilityGerm-Line MutationGoalsHumanImageInbred BALB C MiceIncidenceIndividualInheritedIntuitionKnockout MiceKnowledgeLeadLi-Fraumeni SyndromeLoss of HeterozygosityMalignant NeoplasmsModelingMolecularMosaicismMusMutatePatientsPenetrancePopulationPredispositionPrevalenceRare DiseasesRiskRisk FactorsScanningSiblingsStudy modelsSunburnSurvival AnalysisTP53 geneTechniquesTestingTherapeutic InterventionTimeTranslatingTumor Suppressor GenesVariantWorkZebrafishcancer riskcohortdesignearly onsetexperiencein vivomelanomamouse modelmutantnovelnovel therapeuticspredictive markerresponsesarcomatumortumorigenesis
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。
项目成果
期刊论文数量(0)
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John M Parant其他文献
John M Parant的其他文献
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{{ truncateString('John M Parant', 18)}}的其他基金
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UAB 儿童囊性肾病核心中心 (UAB-CCKDCC) - 体外生物测定和模型开发资源
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10218163 - 财政年份:2020
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UAB Childhood Cystic Kidney Disease Core Center (UAB-CCKDCC) - In Vitro Bioassay and Model Development Resource
UAB 儿童囊性肾病核心中心 (UAB-CCKDCC) - 体外生物测定和模型开发资源
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10685989 - 财政年份:2020
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UAB Childhood Cystic Kidney Disease Core Center (UAB-CCKDCC) - In Vitro Bioassay and Model Development Resource
UAB 儿童囊性肾病核心中心 (UAB-CCKDCC) - 体外生物测定和模型开发资源
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10455720 - 财政年份:2020
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Deciphering How Esco2 Loss Acts as a Penetrance Modifier
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9888342 - 财政年份:2017
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Light-Induced Genetic Alterations within Single Cell of a Live Vertebrate Animal
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8831293 - 财政年份:2014
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Light-Induced Genetic Alterations within Single Cell of a Live Vertebrate Animal
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