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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。