MOLECULAR GENETICS OF WILMS' TUMOR

肾母细胞瘤（WT）是一种儿童肾脏肿瘤， 在家庭中。 只有少数基因被认为是重要的， WT的病因学，使其成为研究体细胞作用的理想模型。 和癌基因突变。两个基因，一个是未定位的 一个是家族易感基因，另一个是最近分离的染色体 11p13基因（WT1），已知在发育中起关键作用， 重量然而，任何一个位点的突变在多大程度上是重要的， 肿瘤发生的原因尚不清楚。 项目9的目标是定义角色 在WT和WT相关的 泌尿生殖系统（GU）异常，并定位家族性WT 易感基因 这将通过分析WT案例来实现 对于WT1基因座的突变，2）通过表征那些WT1突变， （3）WT家系的遗传连锁分析。患者DNA样本 将筛选体细胞和胚细胞的大基因重排， 微缺失和点突变。将对检测到的突变进行测序 并进一步表征了基因内的位置和类型 突变（缺失或点突变，转换或颠换， 错义或无义，蛋白质产物缺失或改变，显性或 隐性）和突变等位基因的亲本起源。本地化 家族易感基因，来自WT家族个体的DNA将 分析疾病表型的遗传连锁， 遍布整个基因组的标记。 这些数据将表明l）有多重要 WT1基因的突变在WT病例中总体存在，在WT相关病例中也存在。 GU异常，2）WT1突变的位置、类型和亲本来源， 3)WT1突变的类型和位置与 观察到的表型，和4）家族性WT基因的位置。这些 然后，数据将为理解这种关系奠定基础，如果有的话， 在这两个WT基因之间，从而阐明了在分子遗传学上， 水平的机制，其中两个基因的行动，无论是独立或在 音乐会，废除细胞生长的正常控制， 分化

Wilms' tumor (WT), a childhood kidney neoplasm, occurs both sporadically and in families. Only a few genes are thought to be important in the etiology of WT, making it an ideal model for studying the role of somatic and germinal mutations in human cancer. Two genes, one an unmapped familial predisposition gene and the other a recently isolated chromosome 11p13 gene (WT1), are known to play a critical role in the development of WT. However, the extent to which mutations at any one locus are important for tumorigenesis is unknown. The goal of Project 9 is to define the role of germinal and somatic mutations at the WT1 locus in WT and WT-associated genitourinary (GU) anomalies and to localize the familial WT predisposition gene. This will be accomplished l) by analyzing WT cases for mutations at the WT1 locus, 2) by characterizing those WT1 mutations, and 3) by genetic linkage analysis of WT families. Patient DNA samples will be screened for somatic and germinal large genetic rearrangements, microdeletions, and point mutations. Detected mutations will be sequenced and further characterized with regard to the intragenic location and type of mutation (deletion or point mutation, transition or transversion, missense or nonsense, absent or altered protein product, dominant or recessive) and the parental origin of the mutant allele. To localize the familial predisposition gene, DNA from individuals from WT families will be analyzed for genetic linkage of the disease phenotype with polymorphic markers throughout the genome. These data will indicate l) how important mutations at the WT1 gene are in WT cases overall and also in WT-related GU anomalies, 2) the location, type, and parental origin of WT1 mutations, 3) the relationship between the type and location of WT1 mutations and the observed phenotypes, and 4) the location of the familial WT gene. These data will then set the stage to understanding the relationship, if any, between these two WT genes, thereby elucidating at the molecular genetic level the mechanism by which two genes act, either independently or in concert, to abrogate normal control of cellular growth and differentiation.