Towards Understanding Prostate Cancer Heterogeneity

理解前列腺癌的异质性

基本信息

批准号：
8506437
负责人：
MARK A. RUBIN
金额：
$ 40.87万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506437
关键词：
6q21 AKT1 gene Accounting Address Affect American Amino Acids Animals B-Lymphocytes Benign Binding Binding Sites Biochemical Biological Assay Biological Models Biology Cancer Etiology Cancer Patient Cell Line Cells Cessation of life Characteristics Cleaved cell Clinical Collaborations Collection Complex DNA Sequence Rearrangement Data Development Disease Disease Progression Dominant-Negative Mutation ERG gene Epidemiology Event Family Frequencies Future Gene Expression Gene Fusion Gene Proteins Genes Genetic Genomics Goals Heterogeneity Hot Spot Human Human Cell Line Immune Interleukin 2 Receptor Knock-out Lead Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Michigan Missense Mutation Molecular Molecular Abnormality Molecular Biology Molecular Profiling Mus Mutate Mutation Natural Killer Cells Nature Neoplasm Metastasis Oncogenes Other Genetics Outcome PTEN gene Pathway interactions Patients Play Point Mutation Population Prevalence Primary Neoplasm Prostate Protein Binding Proteins Proteomics Proto-Oncogene Proteins c-akt Published Comment Publishing Recruitment Activity Recurrence Reporting Research Design Research Personnel Resistance Resources Risk Role Sampling Second Primary Cancers Series Signal Pathway Structural Protein Substrate Interaction Substrate Specificity T-Lymphocyte Subsets TMPRSS2 gene TP53 gene Testing Tissues Translations Transplantation Universities Work base cellular engineering cohort design gain of function high risk in vivo in vivo Model interest loss of function loss of function mutation men mouse model mutant novel outcome forecast prostate cancer model protein function protein structure public health relevance red fluorescent protein skills structural biology tissue regeneration tumor tumor growth ubiquitin ligase ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Protein-altering point mutations are uncommon in prostate cancer. The overall and protein-altering mutation rate of primary prostate cancer is among the lowest reported, approximately an order of magnitude lower than other cancers. Consistent with this, recurrent protein-altering mutations are rare in prostate cancer. Mutations in AR, PTEN, and AKT1 are among the most common; these occur rarely in primary prostate cancer, with reported frequency around 1%. The SPOP gene (Speckle-type POZ Protein) encodes for the substrate-recognition component of a Cullin3- based E3-ubiquitin ligase. Mutations in SPOP in prostate cancer were recently reported in two systematic sequencing studies. We have identified the presence of recurrent mutations in SPOP in 6-13% of human prostate cancers in multiple independent patient cohorts (Barbieri et al., Nature Genetics 2012). Recurrent missense mutations were found exclusively in the structurally-defined substrate-binding cleft of SPOP, and structural analysis suggests that these mutations will inactivate SPOP function by disrupting SPOP-substrate interaction. Further, we found that loss of SPOP function in prostate cell lines resulted in increased invasion, and altered gene expression; evidence of this expression signature was identified in primary tumors harboring SPOP mutation. Importantly, all SPOP mutations occurred in tumors that were negative for ERG rearrangement and PTEN deletion; these tumors displayed characteristic somatic copy number aberrations. Taken together, these findings support a distinct molecular class of prostate cancer. The overall goal of this proposal is to define the role of SPOP mutations in prostate cancer and elucidate the biology of SPOP mutant prostate cancer as a distinct molecular subclass. We propose three specific Aims that together will examine the substrate specificity of SPOP mutant proteins, test the common SPOP mutations in an in vivo model of prostate cancer, identify cooperating and mutually exclusive genetic events, and examine the impact of SPOP mutation on prostate cancer patients. We will use a combination of biochemical, structural biology, in vivo and molecular biology approaches to study these events in prostate cancer models systems, while also employing large cohorts of primary and metastatic human prostate cancer samples to integrate genetic and epidemiologic analyses. Furthermore, we have assembled an outstanding team of co- investigators with complementary skills and resources to execute these proposed studies.

描述（由申请人提供）：蛋白质改变点突变在前列腺癌中并不常见。原发性前列腺癌的总体突变率和蛋白质改变突变率是报道的最低之一，大约比其他癌症低一个数量级。与此一致的是，复发性蛋白质改变突变在前列腺癌中很少见。 AR、PTEN 和 AKT1 突变是最常见的突变；这些在原发性前列腺癌中很少发生，据报道频率约为 1%。 SPOP 基因（斑点型 POZ 蛋白）编码基于 Cullin3 的 E3 泛素连接酶的底物识别组件。最近两项系统测序研究报告了前列腺癌中 SPOP 的突变。我们在多个独立患者队列中发现 6-13% 的人类前列腺癌中存在 SPOP 复发突变（Barbieri 等人，Nature Genetics 2012）。反复发生的错义突变仅在 SPOP 结构确定的底物结合裂隙中发现，结构分析表明这些突变将通过破坏 SPOP-底物相互作用来失活 SPOP 功能。此外，我们发现前列腺细胞系中 SPOP 功能的丧失导致侵袭增加和基因表达改变；在携带 SPOP 突变的原发性肿瘤中发现了这种表达特征的证据。重要的是，所有 SPOP 突变都发生在 ERG 重排和 PTEN 缺失呈阴性的肿瘤中；这些肿瘤表现出特征性体细胞拷贝数畸变。总而言之，这些发现支持前列腺癌的独特分子类别。该提案的总体目标是定义 SPOP 突变在前列腺癌中的作用，并阐明 SPOP 突变前列腺癌作为独特分子亚类的生物学特性。我们提出了三个具体目标，共同检查 SPOP 突变蛋白的底物特异性，测试前列腺癌体内模型中常见的 SPOP 突变，识别协同和相互排斥的遗传事件，并检查 SPOP 突变对前列腺癌患者的影响。我们将结合使用生化、结构生物学、体内和分子生物学方法来研究前列腺癌模型系统中的这些事件，同时还采用大量原发性和转移性人类前列腺癌样本来整合遗传和流行病学分析。此外，我们还组建了一支由具有互补技能和资源的共同研究人员组成的优秀团队来执行这些拟议的研究。