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

• 批准号: 8381281
• 负责人: Daniel A. Haber
• 金额: $ 26.84万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8381281
• 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; Denys-Drash Syndrome; 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; 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; 16q; Accounting; Affect; Age; Biological Markers; Biologically Based Therapy; Cell Line; Childhood; Childhood Renal Neoplasm; Clinical; Clinical Management; Complement; Dana-Farber Cancer Institute; Defect; Denys-Drash Syndrome; 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; 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

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.

威尔姆斯肿瘤是最常见的小儿肾癌，与肾脏发育密切相关。 两种基因的Mutafions WT1和β-catenin，以及胰岛素样生长因子2的表观变化2 （IGF2）已经描述了基因座，但大多数病例的遗传基础仍然未知。给出 Wilms肿瘤的当前治疗方案达到了很高的成功率（85％），有紧迫的需求 对于可以指导临床管理但很难定义的预后标记。我们有 最近确定了位于X染色体WTX上的一种新型肿瘤抑制剂，该抑制剂在 威尔姆斯肿瘤病例中有30％。我们现在建议以我们的初步发现建立建立临床相关性的基础 WTX Inacfivafion并测试WTX Mutafions的电力应用作为预后的标志。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 这些研究将通过定义威尔姆斯的新型生物标志物，共同实现立即的翻译目标 肿瘤，并将进一步了解这种疾病，以允许未来基于生物学的发展 疗法。具体目的：1）定义WILMS肿瘤中WTX失活的临床相关性。我们将 分析200个WILMS肿瘤以进行WTX突变，并将我们的发现与疾病结局和其他 临床参数，例如陈述时的年龄，诊断阶段，双边性和相关性 发育畸形。我们还将开发WTX多克隆抗体和Wilms肿瘤Fissue 微阵列测试WTX蛋白水平。 2）建模WTX弹性以识别潜在临床的途径 意义。我们将使用标记的WTX的免疫沉淀，然后进行质谱法来定义 WTX与其他细胞成分之间的相互作用。这些相互作用的功能后果 将使用肾脏衍生的细胞系和在体内使用WTX条件基因敲除小鼠在体外进行验证。 3）新型Wilms肿瘤标记的临床验证。将测试参与WTX相关途径的基因 通过将表达水平与临床参数相关联，适用于生物标志物。我们 还将测试原发性威尔姆斯肿瘤中突变的所选基因。我们预见到这一点，定义 预后标记并促进我们对WILMS肿瘤中与WTX相关途径的了解，该项目将 在治疗小儿肾癌方面有公共卫生应用。