Deciphering How Esco2 Loss Acts as a Penetrance Modifier

解读 Esco2 损失如何作为外显率调节剂

• 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
• 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

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.

摘要 携带杂合性p53胚系突变的Li Fraumeni患者极易患癌症。 这些人的外显率可能有很大的差异；一些人在1岁之前就开始患肿瘤，而 一些在74岁之前没有患上癌症的人。P53是散发性肿瘤中突变最广泛的基因 因此，了解影响肿瘤穿透性的机制将对预防癌症有很大的好处。 判断个人患癌症的风险。我们已经做了独一无二的观察，在两种情况下，单侧ESCO2丢失 斑马鱼和小鼠，加速了p53杂合子动物的肿瘤形成，但不是p53野生型或 纯合的零基因动物。此外，我们观察到ESCO2杂合子缺失动物的细胞比例很高 姐妹染色单体凝聚力(SCC)降低。这些观察结果证实了我们的假设，即 鳞状细胞癌会导致杂合性丢失率增加，从而加速肿瘤的发生和发展 肿瘤的透视性增强。在这项提议中，我们将解决这一假说并破译其机制 ESCO2损失如何起到外显修饰剂的作用。目标1，确定是否存在加速的LH率，以及 在COHE降低的动物肿瘤中，导致加速肿瘤发生的基因组不稳定性类型/S- 目的2，确定肿瘤增强的程度是否依赖于凝聚功能障碍的程度； 目的3，确定在生物化学方面，ESCO2是否通过凝聚力建立因子减少乙酰化 凝聚力降低，肿瘤增强。拟议工作的预期总体影响是，它将 从根本上推进我们对SCC功能障碍如何影响肿瘤发生的机械性理解。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。