Wilms tumor (WT) is a childhood kidney tumor that is a very productive model for understanding the role of genetic alterations and interactions in tumorigenesis. The etiology of WT is genetically heterogeneous. Only one WT gene, WT1, has been identified to date. It is mutated in only 20% of Wilms tumors and is not the predisposing gene segregating in most WT families. Through our work characterizing the molecular anatomy of Wilms tumors in the last funding period, we have identified for the first time new regions of LOH and also patterns of LOH, gene mutation, and microarray gene expression profiles that differ between genetically defined subsets of Wilms tumors. From these data we hypothesize that the rate-limiting steps for the development of WT involve alterations at multiple genes and that different combinations of mutations act together to dysregulate a limited number of cellular pathways that are critical for the regulation of cell proliferation and differentiation in the kidney. With the exception of WT1, the identity of these mutant genes and the abrogated cognate cellular pathway is unknown. Even for WT1-mutant tumors, it is not clear what cellular pathway is dysregulated as a result of WT1 mutation. However, our recent data on genotype-specific patterns of gene mutation and differential gene expression strongly implicate several signaling pathways known to play a role in tumorigenesis. The overall goal in the next funding period is to discover and investigate - guided by our LOH, linkage, mutation and expression data - WT """"""""pathway"""""""" phenotypes in tumors and to determine how alterations at multiple loci/pathways cooperate during tumorigenesis. These investigations will also further our understanding of the molecular genetic architecture and biology of more etiologically complex adult tumors. As the biological pathways discovered for Wilms tumor may be both common and unique to pediatric tumors, the data from our work may well provide additional insights on approaches for targeting these pathways for treatment of both pediatric and adult cancers. Mechanisms that normally control cell growth and development are disrupted in cancer by gene mutations. We will identify how these control mechanisms are mutated in Wilms tumor (WT). The mechanisms identified for WT will likely be those mutated in other cancers, too, and the proposed work will provide insight on approaches for targeting these mechanisms for treatment of both pediatric and adult cancers.
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