FAMILIAL WILMS' TUMOR

Wilms肿瘤（WT）是一种儿童肾脏肿瘤，由于其在儿童早期发育及其通常的整倍体基因组，其是在不存在广泛的非整倍体和混杂的环境影响的情况下研究遗传改变在肿瘤发生中的作用的有价值的模型。WT在家族背景下偶尔发生。WT的家族易感性是异质性的; 11 p13 WT基因，WT 1，可以被排除为大多数WT家族中的易感基因，因为可以在一个大的法裔加拿大家族中与易感性相关的17 q区域。这些数据证明了在大多数WT家族中存在赋予肿瘤易感性的基因。我们已经确定了19q13.4（FWT 2）区域，该区域与几个大型WT家族的易感性有遗传联系。我们还鉴定了FWT 2处的肿瘤特异性杂合性丢失（洛）。值得注意的是，对于来自两个WT家族的个体，其在两个FWT 2上没有遗传连锁，但在FWT 2上观察到肿瘤特异性洛缺失。根据这些数据，我们假设在WT家族中，肿瘤发生的限速步骤涉及至少两个位点的改变。这些改变是通过遗传连锁分析鉴定的可遗传突变和通过洛缺失或突变分析检测的体细胞改变的组合。拟议研究的目标是：1）评价来自19 q连锁和非19 q连锁WT家族的肿瘤中几个基因组区域的相互作用的种系和体细胞改变的发生，以及2）使用19号染色体存在的大量物理和遗传图谱数据以及基因组和cDNA克隆资源亚定位和分离FWT 2基因。将评估WT家族成员的正常和肿瘤组织的19 q连锁、WT 1突变。洛缺失、19 q变异和特定候选FWT 2基因的变异。鉴定受家族性WT中生殖系或体细胞改变影响的基因将使我们能够确定由这些改变废除的生化途径，并确定这些改变是否影响相同或不同的途径。将这些数据与来自肉瘤家族的数据（项目1和4）进行比较，将进一步了解遗传改变在儿童和成人发病肿瘤中的作用。

Wilms tumor (WT) is a childhood kidney tumor which, due to its development in early childhood and its generally euploid genome, is a valuable model for investigating the role of genetic alterations in tumorigenesis in the absence of wide spread aneuploidy and confounding environmental effects. WT occurs both sporadically and in a familial context. Familial predisposition to WT is heterogeneous; the 11p13 WT gene, WT1, can be excluded as the predisposing gene in most WT families as can a 17q region which is linked to predisposition in a large French Canadian family. These data demonstrate the existence of a gene(s) that confers tumor predisposition in most WT families. We have identified a region of 19q13.4 (FWT2) that is genetically linked to predisposition in several large WT families. We have also identified tumor-specific loss of heterozygosity (LOH) at FWT2. Significantly, for individuals from two WT families which are not genetically linked two FWT2, tumor-specific LOH at FWT2 is nevertheless observed. From these data we hypothesize that in WT families, the rate limiting steps in tumorigenesis involve alterations at least two loci. These alterations are a combination of heritable mutations, as identified by genetic linkage analysis, and somatic alterations as detected by LOH or mutational analysis. The goals of the proposed study are 1) to evaluate the occurrence of interacting germline and somatic alterations at several genomic regions in tumors from 19q-linked and non-19q-linked WT families, and 2) to sub-localize and isolate the FWT2 gene using the vast resources of physical and genetic mapping data and genomic and cDNA clones that exist for chromosome 19. Normal and tumor tissue from members of WT families will be assessed for 19q linkage, WT1 mutations. LOH, 19q alterations, and alterations at specific candidate FWT2 genes. Identification of the genes affected by either germline or somatic alterations in familial WT will enable us to define biochemical pathways abrogated by these alterations in familial WT will enable us to define biochemical pathways abrogated by these alterations in familial WT will enable us to define biochemical pathways abrogated by these alterations and determine whether 6the alterations affect the same, or different, pathways. Comparison of these data with those from the sarcoma families (Projects 1 and 4) will provide further insight into the role of genetic alterations in both childhood and adult-onset tumors.