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Identification of novel genes involved in the genesis of Wilms tumor of the kidney.

机译：鉴定涉及肾脏肾母细胞瘤发生的新基因。

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摘要

Wilms tumor is the most common form of childhood renal tumor with an estimated incidence of 1 in 10 000 live births. Overall survival is good, exceeding 85% with current therapies; however, a subset of children are resistant to treatment and eventually succumb to their disease. Only one gene, WT1, has been cloned and proven to be involved in the etiology of Wilms tumor. However, defects in this gene account for only approximately 10--20% of sporadic Wilms tumors indicating that Wilms tumors are genetically heterogeneous. Identification of genes involved in the initiation or and/or progression of Wilms tumor is needed in order to gain a better understanding of this cancer and aid in the development of prognostic factors and refinement of current therapies. Therefore, our global objective was to identify and characterize candidate Wilms tumor genes using a combination of methodologies.;The Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth syndrome in which individuals are predisposed to the development of Wilms tumor. Defects in the gene, GPC3, give rise to SGBS. Therefore, we hypothesized that some tumors from non-SGBS individuals may harbor GPC3 mutations. We conducted an extensive mutation analysis of the GPC3 gene in 64 Wilms tumors. However, it was found that defects in the GPC3 gene in non-syndrome-associated Wilms tumors were not a common occurrence.;Approximately 20% of Wilms tumors lose heterozygosity of chromosome 16q and this loss is associated with poor prognosis. We therefore proposed to identify Wilms tumor gene(s) on chromosome 16q and/or its downstream targets utilizing differential display PCR and an in silico approach of database searching. Ksp-cadherin was identified in silico as a strong Wilms tumor candidate gene and was further evaluated in 34 Wilms tumors. Interestingly, Ksp-cadherin RNA and protein was found to be expressed in all fetal and mature kidney tested but was absent in the majority of Wilms tumors evaluated. These results suggest that loss of Ksp-cadherin expression may be involved in the pathogenesis of Wilms tumor and warrants further evaluation.
机译：Wilms肿瘤是儿童肾脏肿瘤的最常见形式，估计每10 000例活产中就有1例发生。总体生存率良好，目前的疗法超过85％；然而，一部分儿童对治疗有抗性，最终屈服于他们的疾病。仅克隆了一个基因WT1，并证明它与Wilms肿瘤的病因有关。但是，该基因的缺陷仅占散发性威尔姆斯肿瘤的约10--20％，这表明威尔姆斯肿瘤在遗传上是异质的。为了更好地理解该癌症并帮助发展预后因素和改进当前疗法，需要鉴定参与Wilms肿瘤的起始或/和进展的基因。因此，我们的全球目标是使用多种方法结合来​​鉴定和表征候选威尔姆斯肿瘤基因。辛普森-戈拉比-贝梅尔综合征（SGBS）是一种过度生长综合征，其中个体易患威尔姆斯肿瘤。基因GPC3的缺陷会导致SGBS。因此，我们假设非SGBS个体的某些肿瘤可能带有GPC3突变。我们对64种Wilms肿瘤中的GPC3基因进行了广泛的突变分析。然而，发现非综合征相关的Wilms肿瘤中GPC3基因的缺陷并不常见。；约20％的Wilms肿瘤失去了16q染色体的杂合性，这种丧失与预后不良有关。因此，我们提出利用差异显示PCR和计算机搜索数据库方法来鉴定染色体16q和/或其下游靶标上的Wilms肿瘤基因。 Ksp-钙粘着蛋白在计算机上被鉴定为强力的Wilms肿瘤候选基因，并在34种Wilms肿瘤中得到了进一步评估。有趣的是，发现Ksp-钙黏着蛋白RNA和蛋白在所有经测试的胎儿和成熟肾脏中都有表达，但在大多数被评估的Wilms肿瘤中却没有。这些结果表明，Ksp-钙黏着蛋白表达的丧失可能与Wilms肿瘤的发病机制有关，需要进一步评估。

著录项

  • 作者

    Gillan, Tanya L.;

  • 作者单位

    University of Alberta (Canada).;

  • 授予单位 University of Alberta (Canada).;
  • 学科 Health Sciences Oncology.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 290 p.
  • 总页数 290
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 老年病学;
  • 关键词

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