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病变，是儿童最常见的实体恶性肿瘤之一。疾病可发生在一个或两个肾脏，大约8%的病例是双侧的。这种肿瘤的病因中有遗传成分的说法来自于几项观察。首先，双侧疾病与发病年龄早有关。其次，双侧肿瘤在有肾母细胞瘤家族史和伴有先天性异常的患者中发病率较高。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恶性肿瘤易感性之间关系的模型。虽然已经克隆出了一种淋巴腺瘤的基因（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。其他几个基因座与Wilms肿瘤的病因学有关，包括7p15-21位点，该位点被证明与15-25%的Wilms肿瘤病例有关，这强烈表明该疾病的肿瘤抑制基因必须位于该区域。由于纯合缺失是肿瘤抑制基因的标志，在7p15-21位点的Wilms肿瘤中已经描述了纯合缺失，我们现在已经描述了这种缺失的程度，作为鉴定Wilms肿瘤抑制基因的第一步，使用非常强大的突变分析技术（DHPLC）和大量的Wilms肿瘤队列，包括那些我们已经确定在7p15-21位点显示杂合性缺失的肿瘤。通过研究这种基因的表达模式，我们将能够确定产生这些肿瘤的干细胞群。了解允许这些细胞逃避正常生长调节的遗传事件的本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.