Clinical Correlations of WTX Inactivation in Wilms Tumor

肾母细胞瘤中 WTX 失活的临床相关性

• 批准号: 7742536
• 负责人: Daniel A. Haber
• 金额: $ 27.02万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742536
• 关键词: 16q; Accounting; Affect; Age; Biological Markers; Biologically Based Therapy; Cell Line; Childhood; Childhood Renal Neoplasm; Clinical; Clinical Management; Complement; Dana-Farber Cancer Institute; Defect; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Disease Outcome; Embryo; Frasier Syndromes; Funding; Future; Gene Silencing; Generations; Genes; Genetic; Genitourinary system; Genomics; Goals; Health; Histology; Immunoprecipitation; In Vitro; Insulin-Like Growth Factor II; Kidney; Kidney Neoplasms; Knockout Mice; Knowledge; Laboratories; Language; Malignant Neoplasms; Mass Spectrum Analysis; Methods; Mission; Modeling; Molecular; Mus; Mutation; Nephroblastoma; North America; Outcome; Pathway interactions; Primary Neoplasm; Prognostic Marker; Protein Binding; Proteins; Public Health; Public Health Applications Research; Renal carcinoma; Reproduction spores; Research; Research Design; Research Personnel; Resolution; Specimen; Stage at Diagnosis; TP53 gene; Techniques; 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; design; in vivo; in vivo Model; malformation; nephrogenesis; novel; outcome forecast; polyclonal antibody; programs; protein expression; success; tumor; tumorigenesis

Stale the application's broad, long-term objectives and specific aims, making reference to ttie health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public infonnation. Therefore, do not include proprietary/confidential infonnation. DO NOT EXCEED THE SPACE PROVIDEO 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.

确定应用程序的广泛、长期目标和具体目标，并参考与健康的相关性 项目（即与机构使命的相关性）。简明地描述实现这些目标的研究设计和方法。描述 您将用于实现这些目标的基本原理和技术。 此外，用两到三个句子，用通俗易懂的语言描述这项研究与公共卫生的相关性。如果申请获得资助，这 描述将按原样成为公共信息。因此，请勿包含专有/机密信息。不要超出空间 提供视频 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，以便未来基于生物学的发展 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，以确定潜在的临床途径 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。