Deciphering How Esco2 Loss Acts as a Penetrance Modifier

解读 Esco2 损失如何作为外显率调节剂

基本信息

批准号：
9888342
负责人：
John M Parant
金额：
$ 42.67万
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：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888342
关键词：
Acetylation Acetyltransferase Address Age Age-Years Alleles Anaphase Animal Model Animals Biochemical Biochemical Pathway Cancer-Predisposing Gene Carbon Dioxide Cells Centrioles Chromosomes Data Daughter Defect Disease Early Diagnosis Event Foundations Frequencies Functional disorder Future General Population Genes Genetic Genetic Screening Genome Genomic Instability Genomics Germ-Line Mutation Human Individual Inherited Knockout Mice Knowledge Lasso Li-Fraumeni Syndrome Loss of Heterozygosity Malignant Neoplasms Metaphase Mitotic Recombination Modeling Molecular Mothers Mus Mutate Outcome Patients Penetrance Population Predisposition Prevalence Process Rare Diseases Risk Factors Roberts-SC phocomelia syndrome Role S Phase Sister Chromatid TP53 gene Testing The Cancer Genome Atlas Therapeutic Intervention Tumor Suppressor Genes Work Zebrafish base cancer risk chromosome loss cohesion daughter cell early onset follow-up homologous recombination mouse model mutant novel novel therapeutics predictive marker response sarcoma tumor tumor initiation 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 pre- dicting individual cancer risk. We have made the unique observation that haploinsufficient Esco2 loss, in both zebrafish and mouse, accelerated tumor formation in a p53 heterozygous animals, but not p53 wild type or homozygous null animal. In addition we observe a high proportion of cells in Esco2 heterozygous null animals to have reduced sister chromatid cohesion (SCC). These observations establish our hypothesis that reduced SCC results in increased rates of loss of heterozygosity, which accelerates the timing of tumor initiation and enhanced tumor penetrance. Within this proposal we will address this hypothesis and decipher the mechanism of how Esco2 loss acts as a penetrance modifier. Aim 1, determine if there are accelerated LOH rates, and the type/s of genomic instability that drive accelerated tumorigenesis, in tumors from animals with reduced cohe- sion; Aim 2, determine if the extent of tumor enhancement is dependent on the extent of cohesion dysfunction; Aim 3, determine if biochemically if reduced acetylation by the cohesion establishment factor, ESCO2 lends to reduced cohesion and tumor enhancement. The expected overall impact of the proposed work is that it will fundamentally advance our mechanistic understanding of a how SCC dysfunction impacts tumorigenesis. This will serve as the foundation for future therapeutic intervention and predictive biomarkers of cancer risk.

抽象的 Li Fraumeni 患者携带 p53 种系杂合突变，极易患癌症。这些人的外显率差异很大；有些人在一岁之前就患有肿瘤，而一些人在 74 岁时并未出现癌症。P53 是散发性癌症中最广泛的突变基因因此，了解影响肿瘤外显率的机制将对预防癌症有很大帮助。预测个人癌症风险。我们进行了独特的观察，即单倍体 Esco2 损失不足，在斑马鱼和小鼠，加速了 p53 杂合动物的肿瘤形成，但不是 p53 野生型或纯合无效动物。此外，我们在 Esco2 杂合无效动物中观察到高比例的细胞降低姐妹染色单体凝聚力 (SCC)。这些观察结果证实了我们的假设，即减少了 SCC 导致杂合性丢失率增加，从而加速肿瘤发生和发生的时间增强肿瘤外显率。在这个提案中，我们将解决这个假设并破译其机制 Esco2 损失如何充当外显率调节剂。目标 1，确定是否存在加速的 LOH 率，以及在粘聚力降低的动物肿瘤中，驱动加速肿瘤发生的基因组不稳定性类型锡安；目标 2，确定肿瘤增强的程度是否依赖于内聚功能障碍的程度；目标 3，通过生化确定 ESCO2 是否通过内聚建立因子减少乙酰化内聚力降低和肿瘤增强。拟议工作的预期总体影响是从根本上增进我们对鳞状细胞癌功能障碍如何影响肿瘤发生的机制的理解。这将作为未来治疗干预和癌症风险预测生物标志物的基础。