Molecular Cloning of the Wilms tumor Gene from 7p15-21

7p15-21 肾母细胞瘤基因的分子克隆

• 批准号: 6684394
• 负责人: KHALID SOSSEY-ALAOUI
• 金额: $ 17.37万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684394
• 关键词: Wilms' tumor; biotechnology; disease /disorder etiology; gene deletion mutation; gene expression; high performance liquid chromatography; human genetic material tag; human tissue; loss of heterozygosity; molecular cloning; neoplasm /cancer genetics; nucleic acid denaturation; polymerase chain reaction; serial analysis of gene expression; tumor suppressor genes

DESCRIPTION (provided by applicant): Wilms tumor is pediatric lesion of the kidney and is one of the most common solid malignancies of the childhood. Disease can occur in one or both kidneys, approximately 8% of cases being bilateral. The suggestion of a genetic component in the etiology of the tumor has come from several observations. Firstly, bilateral disease is associated with an early age of onset. Secondly, there is a high incidence of bilateral tumors in cases with a family history of Wilms tumor and in patients with associated congenital anomalies. Histological features indicate that the tumor occurs as a result of aberrant embryological development of the kidney. The kidney is therefore a model for studying the association between processes involved in tissue development and predisposition to malignancy. Although a gene for Wilms tumor (WT1) has been cloned, less than 10% of cases could be explained by mutations and/or alterations of this gene. Several other loci have been implicated in the etiology of Wilms tumors, including the 7p15-21 locus which was shown to be involved in 15-25% of Wilms tumors cases, strongly suggesting that a tumor suppressor gene for this disease must lie within this region. Since homozygous deletions are hallmarks of tumor suppressor genes, a homozygous deletion has been described in a Wilms tumor within the 7p15-21 locus and we have now characterized the extent of this deletion as a first step towards the identification of the Wilms tumor suppressor gene using a very powerful mutation analysis technology (DHPLC) and a large cohort of Wilms tumors, including those tumors that we have identified to show loss of heterozygosity at the 7p15-21 locus. By studying the expression pattern of this gene we will be able to identify the population of stem cells which give rise to these tumors. Understanding the nature of the genetic events which allow these cells to escape their normal growth regulation may also provide an opportunity for therapeutic intervention.

描述（由申请人提供）：Wilms肿瘤是肾脏的儿科病变，是童年最常见的固体恶性肿瘤之一。疾病可能发生在一个或两个肾脏中，大约8％的双侧病例。肿瘤病因中遗传成分的建议来自几种观察结果。首先，双侧疾病与发病年龄有关。其次，患有威尔姆斯肿瘤家族史和相关先天异常的患者的病例中，双侧肿瘤发生率很高。组织学特征表明肿瘤是由于肾脏异常发育而发生的。因此，肾脏是研究组织发育涉及的过程与恶性肿瘤易感性之间的关联的模型。尽管已经克隆了Wilms肿瘤的基因（WT1），但只有不到10％的病例可以通过该基因的突变和/或改变来解释。其他几个基因座也与威尔姆斯肿瘤的病因有关，其中包括7p15-21基因座，该基因座被证明与15-25％的威尔姆斯肿瘤病例有关，强烈表明该疾病的肿瘤抑制基因必须在该地区内。由于纯合缺失是肿瘤抑制基因的标志，因此在7p15-21基因座的Wilms肿瘤中已经描述了纯合缺失，我们现在将这种缺失的程度描述为鉴定Wilms肿瘤基因使用Wilms肿瘤基因的第一步。非常强大的突变分析技术（DHPLC）和大量的Wilms肿瘤，包括我们确定的那些肿瘤，这些肿瘤显示出7p15-21基因座的杂合性丧失。通过研究该基因的表达模式，我们将能够鉴定出引起这些肿瘤的干细胞群体。了解允许这些细胞逃脱其正常生长调节的遗传事件的性质也可能为治疗干预提供了机会。