Genes disrupted be a t(5;6) in a Wilms Tumor Patients

描述(申请人提供)：肾母细胞瘤是最常见的儿科癌症之一，也是全球儿童癌症死亡的主要原因。肾母细胞瘤既有家族性的，也有散发性的，一般认为是由分化失败引起的持续性后肾胚芽所致。WT1基因是在10多年前发现的，尽管几个实验室做出了努力，但它仍然是已知的与Wilms‘s肿瘤有关的唯一肿瘤抑制基因。然而，WT1在不到10%的病例中涉及，这表明肯定涉及其他基因。对染色体重排断点的分析，特别是易位，在发现与癌症有关的新基因方面取得了极其成功的成果。本申请中提出的研究的目标是确定在双侧肾母细胞瘤患者中发现的一个或多个受明显平衡的t(5；6)(Q21；Q21)影响的基因，并测试这些基因是否与我们的肾母细胞瘤小组有关。6q21区域参与了另外三例与肾母细胞瘤相关的易位病例，并且很可能含有相关基因(S)。这种重排产生的两条衍生染色体被分离成体细胞杂交体，这为精确定位5号和6号染色体上的断裂区提供了强大的试剂。 这项建议的具体目标是： 1.精确定位双侧肾母细胞瘤患者t(5；6)(q21；q21)重排断裂点。 2.鉴定与肾母细胞瘤相关的t(5；6)(q21；q21)基因(S)。 3.分析我们收集的肾母细胞瘤中特定目的基因的突变、重排、启动子甲基化和表达变化2.识别与肾母细胞瘤的病因有关的新基因将有助于阐明分化的肾细胞在发育过程中发生转化的机制。此外，这些基因的特征可能为诊断和治疗这种癌症提供新的机会。

DESCRIPTION (provided by applicant): Wilms' tumor of the kidney is one of the most common pediatric cancers and is a leading cause of cancer mortality in children worldwide. Wilms' tumor occurs in both familial and sporadic forms and is believed to arise from persistent metanephric blastema resulting from a failure of differentiation. The WT1 gene was identified more than 10 years ago and, despite the efforts of several laboratories, remains the only tumor suppressor gene known to be involved in Wilms' tumor. However, WT1 is involved in less than 10% of cases suggesting that other genes must be involved. The analysis of chromosome rearrangement breakpoints, particularly translocations, has been extremely successful in the discovery of novel genes involved in cancer. The goals of the studies proposed in this application are to identify the gene or genes affected by an apparently balanced constitutional t(5;6)(q21;q21) identified in a patient with bilateral Wilms' tumor and to test these genes for involvement in our panel of Wilms' tumors. The 6q21 region is involved in three other reported cases of translocations associated with Wilms' tumor and most likely harbors the relevant gene(s). The two derivative chromosomes resulting from this rearrangement have been segregated into somatic cell hybrids which provide powerful reagents to precisely localize the breakpoint regions on chromosome 5 and 6. The specific aims of this proposal are: 1. Precisely locate rearrangement breakpoints of the t(5;6)(q21;q21) in a patient with bilateral Wilms' tumor. 2. Identify the gene(s) disrupted by the Wilms' tumor associated t(5;6)(q21;q21). 3. Analyze our collection of Wilms' tumors for mutations, rearrangements, promoter methylation and altered expression of genes identified in Specific Aim 2. The identification of novel genes that contribute to the etiology of Wilms' tumor will help elucidate the mechanisms by which differentiating kidney cells become transformed during development. Furthermore, the characterization of these genes may provide novel opportunities for diagnosis and treatment of this cancer.