Molecular Genetic Pathways in Wilms Tumor Development

University Of Tx Md Anderson Can Ctr, Houston TX

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Abstract

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