TP53 Germline Mutations: Beyond LFS

项目摘要 该提案解决了挑衅性的问题1“什么分子机制影响疾病的发病率 遗传了癌症易感基因的个体的癌症易感性？" 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 神经胶质瘤）、肾上腺皮质癌和其它癌症。编码p53肿瘤抑制因子的TP53发生突变 75%的LFS家庭。LFS患者的TP53突变发生在编码序列（CDS）中，并产生 突变型p53蛋白缺乏大部分或全部正常的肿瘤抑制功能， 特性.除了LFS突变体之外，已知有超过200种TP53的天然存在的种系突变体，但只有一种突变体存在。 它们中的少数引起可测量的p53功能的扰动。最近的报告表明， 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， 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 结直肠腺瘤因此，这种p53非编码突变体的癌症易感性并不严格地反映 LFS患者中的p53生殖系突变。具体地说，这种非编码突变不会增加 乳腺癌是最常见的LFS肿瘤，而它与胶质瘤中的LFS突变体相似 易感性这种p53突变体在已知的癌症易感性等位基因中是独特的，因为它 非编码的并且以较高的频率存在（在一般人群中约1/50，即，超过600万美国人， 全世界有1亿人携带这种突变体）。我们假设p53的适度减少 非编码突变体的活性使携带者易患神经胶质瘤，而不是乳腺癌。本研究 将使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 通过与LFS编码序列突变体进行比较。在目标1中，我们将确定p53突变体是否 增加小鼠神经胶质瘤的发展。在目标2中，我们将确定该突变体在乳腺肿瘤中的作用 在小鼠和人乳腺上皮细胞转化中的发育。在目标3中，我们将剖析 p53 PAS突变体与LFS突变体在肿瘤发生中的机制比较 细胞和神经干细胞。从这项研究中产生的数据将揭示生物学和病理功能， 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影响， 重要性在于，我们的发现将揭示生殖系变异与 组织特异性癌症转移率。

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.