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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。 WT1 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 (IGF2) 基因座已被描述，但大多数病例的遗传基础仍不清楚。给定目前针对肾母细胞瘤的治疗方案取得了很高的成功率（85%），迫切需要寻找可以指导临床管理的预后标志物，但这些标志物很难定义。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。我们现在建议以我们的初步发现为基础，建立以下临床相关性： WTX 失活并测试 WTX 突变作为预后标志物的潜在应用。我们会还通过识别受 WTX 失活影响的分子途径来定义其他标记这些研究将共同通过在威尔姆斯中定义新颖的生物标志物来实现直接的转化目标肿瘤，并将进一步加深我们对这种疾病的了解，以实现基于生物学的未来发展疗法。具体目标： 1) 确定肾母细胞瘤中 WTX 失活的临床相关性。我们将分析 200 个肾母细胞瘤的 WTX 突变，并将我们的发现与疾病结果和其他结果相关联临床参数，例如就诊年龄、诊断分期、双侧性和相关性发育畸形。我们还将开发WTX多克隆抗体和Wilms肿瘤组织微阵列检测 WTX 蛋白水平。 2) 对WTX功能进行建模以识别潜在的临床途径意义。我们将使用标记的 WTX 进行免疫沉淀，然后进行质谱分析来定义 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使用肾源性细胞系进行体外验证，并使用 WTX 条件敲除小鼠进行体内验证。 3）新型Wilms肿瘤标志物的临床验证。涉及WTX相关途径的基因将被测试通过将表达水平与临床参数相关联，作为生物标志物的潜在临床应用。我们还将测试原发性肾母细胞瘤中选定基因的突变。我们预计，通过定义预后标志物并加深我们对肾母细胞瘤中 WTX 相关通路的了解，该项目将在治疗小儿肾癌方面具有公共卫生应用。