MOLECULAR PATHOLOGY OF WILMS TUMOR RELATED GENES 11P

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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.