TP53 Germline Mutations: Beyond LFS
TP53 种系突变:超越 LFS
基本信息
- 批准号:10397062
- 负责人:
- 金额:$ 35.87万
- 依托单位:
- 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 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdrenocortical carcinomaAgeAllelesAmericanAnimal ExperimentsApoptosisBasal cell carcinomaBiologicalBrain NeoplasmsBreastBreast Cancer Risk FactorBreast Epithelial CellsCancer-Predisposing GeneCarcinogen exposureCell LineCodeColonic NeoplasmsColorectal AdenomaDataDevelopmentDiseaseERBB2 geneEmbryoEsophageal Squamous Cell CarcinomaFamilyFemaleFibroblastsFoundationsFrequenciesGene FrequencyGeneral PopulationGenesGerm-Line MutationGliomaGliomagenesisHereditary DiseaseHeterozygoteHomozygoteHumanInbred BALB C MiceIncidenceIndividualInheritedLi-Fraumeni SyndromeMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of prostateMammary NeoplasmsMammary TumorigenesisMeasurableMessenger RNAMinorMolecularMusMutateMutationNF1 geneNeuroblastomaNucleotidesOdds RatioOncogenicOrthologous GenePathologicPatientsPenetrancePersonsPlatelet-Derived Growth FactorPolyadenylationPopulationPositioning AttributePredispositionPrevention strategyPropertyReportingRiskRoleSignal TransductionSingle Nucleotide PolymorphismSkinSoft tissue sarcomaSomatic MutationSusceptibility GeneTP53 geneTissuesTransgenic MiceTumor Suppressor ProteinsTumorigenicityUntranslated RNAVariantWild Type MouseWorkcancer cellcancer therapycancer typecell transformationhigh risklifetime riskmalemalignant breast neoplasmmammarymouse modelmutantnerve stem cellnovelosteosarcomaprostate carcinogenesisself-renewalstem cell self renewalstem cellstreatment strategytumortumorigenesisvirtual
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.
项目摘要
这一建议解决了一个具有挑衅性的问题1:什么分子机制影响疾病的外显性
在遗传了癌症易感基因的人身上?Li-Fraumeni综合征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抑癌基因的TP53发生突变
在75%的LFS家庭中。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,通常具有致癌作用
属性。除LFS突变体外,已知的TP53自然发生的种系突变体超过200个,但只有一个
很少有它们对P53功能造成可测量的扰动。最近的报告表明,单一的
TP53非编码区核苷酸多态使携带者易患多种癌症,包括
胶质瘤、神经母细胞瘤、皮肤基底细胞癌、食管鳞癌、前列腺癌和
结直肠腺瘤。因此,这个p53非编码突变体的癌症易感性并不严格反映出
LFS患者P53基因突变的研究具体地说,这种非编码突变不会增加罹患
乳腺癌,最常见的LFS肿瘤,而它与胶质瘤的LFS突变有相似之处
性情。这个p53突变在已知的癌症易感性等位基因中是独一无二的,因为它是
非编码且出现频率更高(在普通人群中约为50%,即超过600万美国人和
全球有1亿人携带这种突变体)。我们假设P53的适度降低
非编码突变体的活性使携带者容易患上胶质瘤,但不会导致乳腺癌。在这项研究中,我们
将利用小鼠模型和细胞系来确定这种P53非编码突变在癌症中的致病作用
将其与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
增加小鼠神经胶质瘤的发展。在目标2中,我们将确定该突变在乳腺肿瘤中的作用
在小鼠和人类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突变体在乳腺癌发生中的作用机制比较
细胞和神经干细胞。这项研究产生的数据将揭示血管内皮细胞的生物学和病理功能
P53胚系突变超出其在LFS中的既定作用。这一项目具有潜在的广泛和深远的影响
重要的是,我们的发现将揭示生殖系变异和
特定于组织的癌症穿透性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Yong Li其他文献
A chimeric vacuolar Na+/H+ antiporter gene evolved by DNA family shuf?ing confers increased salt tolerance in yeast
由 DNA 家族改组进化而来的嵌合液泡 Na /H 逆向转运蛋白基因可增强酵母的耐盐性
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
Yong Li;Hailing Gao;Jiang Wu;Wenzhu Guan - 通讯作者:
Wenzhu Guan
Yong Li的其他文献
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{{ truncateString('Yong Li', 18)}}的其他基金
Optimizing Syngeneic Mouse Models to Target Mutant p53
优化同基因小鼠模型以靶向突变 p53
- 批准号:
10677353 - 财政年份:2023
- 资助金额:
$ 35.87万 - 项目类别:
Cancer Prevention-Interception Against MGUS Progression
癌症预防——阻止 MGUS 进展
- 批准号:
10745010 - 财政年份:2023
- 资助金额:
$ 35.87万 - 项目类别:
Therapeutic Targeting a Non-Hodgkin Lymphoma Driver Using AI
使用人工智能针对非霍奇金淋巴瘤驱动者进行治疗
- 批准号:
10585717 - 财政年份:2022
- 资助金额:
$ 35.87万 - 项目类别:
Modulation of MicroRNAs with Xenobiotics to Target c-Myc
用异生素调节 MicroRNA 以靶向 c-Myc
- 批准号:
10018536 - 财政年份:2019
- 资助金额:
$ 35.87万 - 项目类别:
MYC as a Biomarker in Aggressive Non-Hodgkin Lymphoma
MYC 作为侵袭性非霍奇金淋巴瘤的生物标志物
- 批准号:
10019120 - 财政年份:2019
- 资助金额:
$ 35.87万 - 项目类别:
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