FAMILIAL WILMS' TUMOR

肾母细胞瘤(Wilms Tumor，WT)是一种儿童肾脏肿瘤，由于其早期发育和基因组的整倍体，在缺乏广泛的非整倍体和混杂的环境影响的情况下，是研究基因改变在肿瘤发生中作用的有价值的模型。WT既可零星发生，也可在家族背景下发生。家族性WT的易感性是不同的；在大多数WT家族中，11p13 WT基因WT1可以被排除为易感基因，在一个加拿大法裔大家庭中，17q区域与易感性有关。这些数据表明，在大多数WT家系中存在一个与肿瘤易感性有关的基因(S)。我们已经确定了一个19q13.4(FWT2)区域，该区域与几个WT大家系的易感性有关。我们还鉴定了FWT2的肿瘤特异性杂合性丢失(LOH)。值得注意的是，对于没有两个FWT2基因连锁的两个WT家族的个体，仍然可以观察到FWT2的肿瘤特异性LOH。根据这些数据，我们假设在WT家族中，肿瘤形成的限速步骤涉及至少两个基因座的改变。这些改变是通过遗传连锁分析鉴定的可遗传突变和通过杂合性缺失或突变分析检测到的体细胞改变的组合。这项研究的目标是：1)评估19q连锁和非19q连锁WT家系肿瘤几个基因组区域的相互作用的生殖系和体细胞改变的发生情况；2)利用大量的物理和遗传图谱数据以及19号染色体的基因组和cDNA克隆，对FWT2基因进行亚定位和分离。WT家族成员的正常和肿瘤组织将被评估19q连锁和WT1突变。LOH，19q改变，以及特定候选FWT2基因的改变。识别家族性WT中受生殖系或躯体改变影响的基因将使我们能够定义被这些改变所消除的生化途径将使我们能够定义被这些改变所消除的生化途径将使我们能够定义被这些改变所消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。将这些数据与肉瘤家族(项目1和项目4)的数据进行比较，将进一步深入了解基因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.