TP53 Germline Mutations: Beyond LFS

TP53 种系突变：超越 LFS

• 批准号: 9912116
• 负责人: Yong Li
• 金额: $ 36.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912116
• 关键词: Accounting; Address; Adrenocortical carcinoma; Age; Alleles; American; Animal Experiments; Apoptosis; Basal cell carcinoma; Biological; Brain Neoplasms; Breast; Breast Cancer Risk Factor; Breast Epithelial Cells; Cancer-Predisposing Gene; Carcinogen exposure; Cell Line; Code; Colonic Neoplasms; Colorectal Adenoma; Data; Development; Disease; ERBB2 gene; Embryo; Esophageal Squamous Cell Carcinoma; Family; Female; Fibroblasts; Foundations; Frequencies; Gene Frequency; General Population; Genes; Germ-Line Mutation; Glioma; Gliomagenesis; Hereditary Disease; Heterozygote; Homozygote; Human; Inbred BALB C Mice; Incidence; Individual; Inherited; Li-Fraumeni Syndrome; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of prostate; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Measurable; Messenger RNA; Minor; Molecular; Mus; Mutate; Mutation; NF1 gene; Neuroblastoma; Nucleotides; Odds Ratio; Oncogenic; Orthologous Gene; Pathologic; Patients; Penetrance; Platelet-Derived Growth Factor; Polyadenylation; Population; Positioning Attribute; Predisposition; Prevention strategy; Property; Protein p53; Reporting; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; Skin; Soft tissue sarcoma; Somatic Mutation; Susceptibility Gene; TP53 gene; Tissues; Transgenic Mice; Tumor Suppressor Proteins; Tumorigenicity; Untranslated RNA; Variant; Wild Type Mouse; Work; cancer cell; cancer therapy; cancer type; cell transformation; high risk; lifetime risk; male; malignant breast neoplasm; mouse model; mutant; nerve stem cell; novel; osteosarcoma; prostate carcinogenesis; self-renewal; stem cells; treatment strategy; tumor; tumorigenesis; virtual

Project Summary This proposal addresses Provocative Question 1 “What molecular mechanisms influence disease penetrance in individuals who inherit a cancer susceptibility gene?” Li-Fraumeni Syndrome (LFS) is a rare, inherited disorder that leads to a higher risk of breast cancer, soft tissue sarcoma, osteosarcoma, brain tumor (including glioma), adrenal cortical carcinoma, and other cancers. TP53, encoding the p53 tumor suppressor, is mutated in ~75% of LFS families. TP53 mutations in LFS patients occur in the coding sequence (CDS) and produce mutant p53 proteins that lack most or all normal tumor-suppressive functions and often confer oncogenic properties. Beyond LFS mutants, over 200 naturally occurring germline mutants of TP53 are known, yet only a few of them cause measurable perturbation of p53 function. Recent reports demonstrate that a single nucleotide polymorphism in a TP53 noncoding region predisposes carriers to multiple types of cancer including glioma, neuroblastoma, skin basal cell carcinoma, esophageal squamous cell carcinoma, prostate cancer, and colorectal adenoma. As such, cancer susceptibility of this p53 noncoding mutant does not strictly mirror that of p53 germline mutations in LFS patients. Specifically, this noncoding mutant confers no increased risk of breast cancer, the most common LFS tumor, whereas it shares similarity with LFS mutants in glioma predisposition. This p53 mutant is positioned uniquely among known cancer-susceptibility alleles in that it is noncoding and present at higher frequency (~1 in 50 in general populations, i.e., over 6 million Americans and 100 million people worldwide carry this mutant). We hypothesize that the moderate reduction of p53 activity by the noncoding mutant predisposes carriers to glioma but not breast cancer. In this study, we will employ mouse models and cell lines to ascertain the causative role of this p53 noncoding mutant in cancer by comparing it with an LFS coding sequence mutant. In Aim 1, we will determine whether the p53 mutant increases glioma development in mice. In Aim 2, we will determine the role of this mutant in mammary tumor development in mice and in human breast epithelial cell transformation. In Aim 3, we will dissect the mechanisms of the p53 PAS mutant in tumorigenesis in comparison with an LFS mutant using mammary stem cells and neural stem cells. Data generated from this study will reveal the biological and pathologic function of p53 germline mutants beyond its established role in LFS. This project has potentially broad and far-reaching significance in that our findings will reveal mechanistic causal connections between germline variation and tissue-specific cancer penetrance.

项目摘要 该提议解决了挑衅的问题1“什么分子机制影响疾病的外观 在继承癌症易感性基因的个人中？ 导致乳腺癌风险更高的疾病，软组织肉瘤，骨肉瘤，脑肿瘤（包括 神经胶质瘤），肾上腺皮质癌和其他癌症。编码p53肿瘤抑制剂的TP53被突变 在约75％的LFS家庭中。 LFS患者的TP53突变发生在编码序列（CD）中并产生 突变体p53蛋白缺乏大多数或所有正常肿瘤抑制功能，并且经常会导致致癌 特性。除了LFS突变体之外，已知的TP53的200多种天然生殖线突变体已知，但只有一个 其中很少引起p53功能的可测量扰动。最近的报告表明一个 TP53非编码区域中的核苷酸多态性使载体易于多种类型的癌症 神经胶质瘤，神经母细胞瘤，皮肤基细胞癌，食管鳞状细胞癌，前列腺癌和 结直肠腺瘤。因此，该p53非编码突变体的癌症易感性并不能严格反映 LFS患者的p53种系突变。具体而言，这种非编码突变体承认没有增加的风险 乳腺癌是最常见的LFS肿瘤，而它与神经胶质瘤中的LFS突变体有相似性 倾向。该p53突变体位于已知的癌症概念等位基因中，因为它是 不编码和以较高的频率存在（一般人口中有50个，即超过600万美国人， 全世界有1亿人携带这个突变体）。我们假设p53的中等减少 通过非编码突变体的活性使载体容易出现神经胶质瘤，而不是乳腺癌。在这项研究中，我们 将采用小鼠模型和细胞系来确定该p53非编码突变体在癌症中的致病作用 通过将其与LFS编码序列突变体进行比较。在AIM 1中，我们将确定p53突变体是否 增加小鼠神经胶质瘤的发育。在AIM 2中，我们将确定该突变体在乳腺肿瘤中的作用 小鼠和人类乳房上皮细胞转化的发育。在AIM 3中，我们将剖析 p53 PAS突变体在肿瘤发生中的机制与LFS突变体相比使用乳腺茎 细胞和神经元干细胞。这项研究产生的数据将揭示 p53种系突变体超出其在LFS中的既定作用。该项目具有潜在的广泛和深远的角度 意义在于我们的发现将揭示种系变化与 组织特异性癌症的外观。