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Towards Understanding Prostate Cancer Heterogeneity

理解前列腺癌的异质性

基本信息

批准号：
9247758
负责人：
MARK A. RUBIN
金额：
$ 5.48万
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 2017-04-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247758
关键词：
6q21 AKT1 gene Address Affect American Amino Acids Animals B-Lymphocytes Benign Binding Binding Proteins Binding Sites Biochemical Biological Assay Biological Models Biology CHD1 gene Cancer Etiology Cancer Patient Cell Line Cells Cessation of life Characteristics Clinical Collaborations Collection Complex Data Development Disease Disease Progression Dominant-Negative Mutation ERG gene Engineering Epidemiology Event Family Frequencies Future Gene Expression Gene Expression Profile Gene Fusion Gene Proteins Genes Genetic Goals Hot Spot Human Human Cell Line Immune Interleukin 2 Receptor Knock-out Lead Lesion Localized Malignant Neoplasm 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 PTEN gene Pathologic Pathway interactions Patient-Focused Outcomes Patients Play Point Mutation Population Prevalence Primary Neoplasm Prostate Proteins Proteomics Proto-Oncogene Proteins c-akt Published Comment Publishing Recruitment Activity Recurrence Reporting Research Design Research Personnel Resistance Resources Risk Role Sampling Series Signal Pathway Substrate Interaction Substrate Specificity T-Lymphocyte TMPRSS2 gene TP53 gene Testing Tissues Transplantation Universities base cancer heterogeneity clinical translation cohort design gain of function genomic aberrations genomic data 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(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和蛋白质改变突变率是报道中最低的之一，大约比其他癌症低一个数量级。与此一致的是，前列腺癌中反复出现的蛋白质改变突变是罕见的。AR、PTEN和AKT1突变是最常见的突变之一；这些突变在原发性前列腺癌中很少发生，报道的频率约为1%。SPOP(斑点状POZ蛋白)编码一种基于Cullin3的E3-泛素连接酶的底物识别成分。前列腺癌的SPOP突变最近在两个系统测序研究中被报道。我们已经在多个独立的患者队列中确定了6-13%的人类前列腺癌中存在SPOP的反复突变(Barbieri等人，《自然遗传学》2012)。反复出现的错义突变仅存在于SPOP的结构定义的底物结合裂隙中，结构分析表明这些突变将通过破坏SPOP与底物的相互作用而使SPOP功能失活。此外，我们发现前列腺细胞系中SPOP功能的丧失导致侵袭性增加和基因表达改变；这种表达特征的证据在携带SPOP突变的原发肿瘤中得到了证实。重要的是，所有SPOP突变都发生在ERG重排和PTEN缺失阴性的肿瘤中；这些肿瘤表现出特征性的体细胞拷贝数异常。综上所述，这些发现支持前列腺癌的一个独特的分子类别。这项建议的总体目标是确定SPOP突变在前列腺癌中的作用，并阐明SPOP突变前列腺癌作为一个独特的分子亚类的生物学。我们提出了三个特定的目标，共同检测SPOP突变蛋白的底物特异性，在前列腺癌体内模型中测试常见的SPOP突变，识别协同和互斥的遗传事件，以及检测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、体内和分子生物学的方法来研究前列腺癌模型系统中的这些事件，同时也使用大量的原发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，我们还组建了一支优秀的合作调查员团队，他们拥有互补的技能和资源，以执行这些拟议的研究。