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

描述(申请人提供)：肾母细胞瘤是儿童肾脏的病变，是儿童最常见的实体恶性肿瘤之一。疾病可以发生在一个或两个肾脏，大约8%的病例是双侧的。肿瘤病因学中的遗传成分的暗示来自于几个观察。首先，双侧疾病与发病年龄较早有关。其次，在有肾母细胞瘤家族史的病例和合并先天性畸形的患者中，双侧肿瘤的发生率较高。组织学特征表明，肿瘤的发生是肾脏胚胎发育异常的结果。因此，肾脏是研究组织发育过程与肿瘤易感性之间关系的模型。虽然Wilms瘤(WT1)的基因已经被克隆，但只有不到10%的病例可以由该基因的突变和/或改变来解释。其他几个基因与肾母细胞瘤的病因有关，包括7p15-21基因座，它被证明与15%-25%的肾母细胞瘤有关，强烈提示该疾病的肿瘤抑制基因一定位于该区域。由于纯合缺失是肿瘤抑制基因的特征，已在Wilms肿瘤中描述了7p15-21基因座内的纯合缺失，我们现在将这种缺失的程度表征为使用非常强大的突变分析技术(DHPLC)和大量Wilms肿瘤的队列来鉴定Wilms肿瘤抑制基因的第一步，包括那些我们已经发现在7p15-21基因座显示杂合性丢失的肿瘤。通过研究该基因的表达模式，我们将能够确定导致这些肿瘤的干细胞群体。了解允许这些细胞逃脱正常生长调控的遗传事件的性质也可能为治疗干预提供机会。

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.