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P1 - Clinical Correlations of WTX Inactivation in Wilms Tumor

P1 - 肾母细胞瘤中 WTX 失活的临床相关性

基本信息

批准号：
8079677
负责人：
Daniel A. Haber
金额：
$ 26.94万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079677
关键词：
16q Accounting Affect Age Biological Markers Biologically Based Therapy Cell Line Childhood Childhood Renal Neoplasm Clinical Clinical Management Complement Defect Development Diagnosis Diagnostic Neoplasm Staging Disease Disease Outcome Embryo Frasier Syndromes Future Gene Silencing Generations Genes Genetic Genitourinary system Goals Histology Immunoprecipitation In Vitro Insulin-Like Growth Factor II Kidney Kidney Neoplasms Knockout Mice Knowledge Laboratories Malignant Neoplasms Mass Spectrum Analysis Modeling Molecular Mus Mutation Nephroblastoma North America Outcome Pathway interactions Primary Neoplasm Prognostic Factor Prognostic Marker Protein Binding Proteins Public Health Applications Research Renal carcinoma Resolution Specimen Stage at Diagnosis TP53 gene Testing Tissue Microarray Treatment Protocols Tumor Markers Tumor Suppressor Genes Tumor Suppressor Proteins Tumor Tissue Tumor stage Validation WT1 gene Work X Chromosome authority base beta catenin clinical application clinically significant comparative genomic hybridization design in vivo in vivo Model malformation nephrogenesis novel outcome forecast polyclonal antibody prognostic protein expression success tumor tumorigenesis

项目摘要

Wilms tumor is the most common pediatric kidney cancer and is closely connected to kidney development. Mutafions in two genes, WT1 and beta-catenin, and epigenefic changes in the insulin-like growth factor 2 (IGF2) locus have been described but the genetic basis of the majority of cases remains unknown. Given that current treatment protocols for Wilms tumor achieve high success rates (85%), there is a pressing need for prognosfic markers that can guide clinical management but these have been difficult to define. We have recently identified a novel tumor suppressor located on the X chromosome, WTX, which is inactivated in 30% of Wilms tumor cases. We now propose to build on our initial findings to establish clinical correlates of WTX inacfivafion and to test the potenfial applicafion of WTX mutafions as markers of prognosis. We wil also define additional markers by identifying molecular pathways that are affected by WTX inactivation Together, these studies will achieve immediate translational goals by defining novel biomarkers in Wilms tumor and will further our understanding of this disease to allow the future development of biologically based therapies. Specific aims: 1) To define clinical correlafions of WTX inactivation in Wilms tumor. We will analyze 200 Wilms tumors for WTX mutations and correlate our findings with disease outcomes and other clinical parameters such as age at presentation, stage at diagnosis, bilaterality and associated developmental malformafions. We will also develop a WTX polyclonal antibody and a Wilms tumor fissue microarray to test WTX protein levels. 2) Modeling WTX funcfion to identify pathways of potential clinical significance. We will use immunoprecipitation of tagged WTX followed by mass spectrometry to define interactions between WTX and other cellular components. The funcfional consequences of these interactions will be validated in vitro using kidney derived cell lines and in vivo using a WTX conditional knockout mouse. 3) Clinical validation of novel Wilms tumor markers. Genes involved in WTX related pathways will be tested for potenfial clinical applicafions as biomarkers by correlafing expression levels with clinical parameters. We will also test selected genes for mutafions in primary Wilms tumors. We anticipated that, by defining prognostic markers and furthering our knowledge of WTX related pathways in Wilms tumor, this project will have public health applications in the treatment of pediatric kidney cancer.

肾母细胞瘤是最常见的儿童肾癌，与肾脏发育密切相关。 WT 1和β-catenin两个基因的突变以及胰岛素样生长因子2的表观遗传变化（IGF 2）基因座的基因已被描述，但大多数情况下的遗传基础仍然未知。给定目前的肾母细胞瘤治疗方案取得了很高的成功率（85%），寻找可以指导临床治疗的特异性标记物，但这些标记物很难定义。我们有最近发现了一种位于X染色体上的新型肿瘤抑制因子，WTX，它在 30%的肾母细胞瘤病例。我们现在建议建立在我们的初步研究结果，以建立临床相关的 WTX基因突变的检测及其作为预后标志物的可能性。我们会还通过鉴定受WTX失活影响的分子途径来确定其他标记物总之，这些研究将通过在Wilms中定义新的生物标志物来实现直接的翻译目标。肿瘤，并将进一步我们对这种疾病的理解，使未来的发展生物为基础的治疗具体目的：1）明确肾母细胞瘤中WTX失活的临床相关性。我们将分析200例肾母细胞瘤的WTX突变，并将我们的发现与疾病结局和其他临床参数，如发病时的年龄、诊断时的分期、双侧性和相关的发育畸形我们还将开发WTX多克隆抗体和Wilms肿瘤裂隙微阵列来测试WTX蛋白水平。2)建模WTX功能，以识别潜在的临床意义我们将使用标记的WTX的免疫沉淀，然后用质谱法来确定 WTX和其他细胞成分之间的相互作用。这些相互作用的功能后果将在体外使用肾脏来源的细胞系和在体内使用WTX条件性敲除小鼠进行验证。 3)新型肾母细胞瘤标志物的临床验证。将检测WTX相关途径中涉及的基因通过将表达水平与临床参数相关联，作为生物标志物用于潜在的临床应用。我们还将检测原发性肾母细胞瘤中选定的基因突变。我们预计，通过定义预后标志物和进一步了解WTX相关通路在肾母细胞瘤，该项目将在儿科肾癌的治疗中具有公共卫生应用。