MOLECULAR PATHOLOGY OF WILMS TUMOR RELATED GENES 11P

肾母细胞瘤（WT）是一种胚胎性肾癌， 一万个孩子 WT是Knudson的两次打击模型的一个范例， 致癌作用，并与此模型一致，11号染色体表现出一种 WT细胞中的肿瘤抑制表型。 WT在某些情况下与 染色体带11p13缺失和WAGR综合征患者 （肾母细胞瘤、无虹膜、泌尿生殖系统发育不良和智力迟钝）， 提示这些基因也定位于染色体11p13。 我们 从酵母人工染色体11p13上克隆了850kb的DNA （YACs），我们已经确定了四个转录序列内， 由散发性WT中的纯合缺失定义的边界。 两个这样 基因表现出发育特异性表达， 在那些重演肾发生早期阶段的肿瘤中表达， 这也是WAGR相关肿瘤的特征。 我们还 将第二个不同的WT基因定位于11p15，如常见的 肿瘤中多态性标记的杂合性缺失区。 此外，我们已经定位了Beckwith-Wiedemann综合征（BWS）基因， 其易患WT和其它胚胎恶性肿瘤，也易患11p15。 我们将分子克隆肾母细胞瘤周围的区域， YACs中11p13的泌尿生殖道发育不良基因，确定候选基因 并描述其中的突变。 我们将 分子克隆BWS基因，并确定其与第二个基因的关系。 WT基因位于11p15。 我们将直接使用YAC来显示肿瘤 候选WT基因的抑制表型。 最后，我们将确定 无论是DNA甲基化还是基因组印记， WT的病理学 这些研究将为理解 WT和染色体邻近疾病的分子机制。 他们 也应该有助于建立一种关系， 发育障碍和恶性肿瘤倾向。

Wilms' tumor (WT) is an embryonal cancer of the kidney affecting one in 10,000 children. WT is a paradigm of Knudson's two-hit model of carcinogenesis, and consistent with this model, chromosome 11 exhibits a tumor suppressor phenotype in WT cells. WT has been associated in some patients with deletions of chromosomal band 11p13 and the WAGR syndrome (Wilms tumor, aniridia, genitourinary dysplasia and mental retardation), suggesting that these genes are also localized to chromosome 11p13. We have cloned 850 kb of DNA from 11p13 in yeast artificial chromosomes (YACs), and we have identified four transcribed sequences within the boundaries defined by a homozygous deletion in a sporadic WT. Two of these genes exhibit developmentally specific expression, and reduced or absent expression in those tumors that recapitulate early stages of nephrogenesis, a feature also characteristic of WAGR-associated tumors. We have also localized a second distinct WT gene to 11p15, as defined by the common region of loss of heterozygosity of polymorphic markers in tumors. Furthermore, we have localized the Beckwith-Wiedemann syndrome (BWS) gene which predisposes to WT and other embryonal malignancies, also to 11p15. We will molecularly clone the region encompassing the Wilms' tumor and genitourinary dysplasia genes of 11p13 in YACs, identify candidate genes for these disorders and characterize mutations in them. We will molecularly clone the BWS gene and determine its relationship to the second WT gene on 11p15. We will use YACs directly to demonstrate a tumor suppressor phenotype of candidate WT genes. Finally, we will determine whether DNA methylation or genomic imprinting plays a role in the molecular pathology of WT. These studies will provide a foundation for understanding the molecular mechanisms of WT and chromosomally adjacent disorders. They should also help to establish a relationship between hereditary developmental disorders and predisposition to malignancy.