TP53 Germline Mutations: Beyond LFS

TP53 种系突变：超越 LFS

基本信息

批准号：
10040324
负责人：
Yong Li
金额：
$ 33.05万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/10040324
关键词：
Accounting Address Adrenocortical carcinoma Age Alleles American Animal Experiments Apoptosis Basal cell carcinoma Biological Brain Brain Neoplasms Breast Breast Cancer Risk Factor Breast Epithelial Cells Cancer-Predisposing Gene Carcinogen exposure Cell Line Code Colonic Neoplasms Colorectal 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 Reporting Risk Role Signal Transduction Single Nucleotide Polymorphism Skin Soft tissue sarcoma Somatic Mutation Susceptibility Gene TP53 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

项目摘要

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.

项目概要该提案解决了挑衅性问题 1“哪些分子机制影响疾病外显率 Li-Fraumeni 综合征 (LFS) 是一种罕见的遗传性疾病？导致乳腺癌、软组织肉瘤、骨肉瘤、脑肿瘤（包括胶质瘤）、肾上腺皮质癌和其他癌症（编码 p53 肿瘤抑制因子）发生突变。 LFS 患者的 TP53 突变发生在约 75% 的 LFS 家族中，并产生编码序列 (CDS)。突变的 p53 蛋白缺乏大部分或全部正常的肿瘤抑制功能，并且通常具有致癌性除了 LFS 突变体之外，已知有 200 多种自然发生的 TP53 种系突变体，但只有一种。其中很少有对 p53 功能造成可测量的扰动。 TP53非编码区的核苷酸多态性使携带者易患多种类型的癌症，包括神经胶质瘤、神经母细胞瘤、皮肤基底细胞癌、食管鳞状细胞癌、前列腺癌和因此，这种 p53 非编码突变体的癌症易感性并不严格反映具体来说，LFS 患者中的 p53 种系突变不会增加患此病的风险。乳腺癌是最常见的 LFS 肿瘤，但它与神经胶质瘤中的 LFS 突变体具有相似性该 p53 突变体在已知的癌症易感性等位基因中具有独特的地位，因为它是非编码且出现频率较高（普通人群中约 50 人中就有 1 人，即超过 600 万美国人和全球有 1 亿人携带这种突变体）我们追求 p53 的适度减少。在这项研究中，非编码突变体的活性使携带者容易患神经胶质瘤，但不会患乳腺癌。将利用小鼠模型和细胞系来确定这种 p53 非编码突变体在癌症中的致病作用通过将其与目标 1 中的 LFS 编码序列突变体进行比较，我们将确定是否是 p53 突变体。增加小鼠神经胶质瘤的发育在目标 2 中，我们将确定该突变体在乳腺肿瘤中的作用。在目标 3 中，我们将剖析小鼠的发育和人类乳腺上皮细胞的转化。与使用乳腺干的 LFS 突变体相比，p53 PAS 突变体在肿瘤发生中的机制这项研究产生的数据将揭示细胞和神经干细胞的生物学和病理功能。 p53 种系突变体超出了其在 LFS 中的既定作用，该项目具有潜在广泛而深远的影响。意义在于我们的发现将揭示种系变异与组织特异性癌症外显率。