Molecular Genetic Pathways in Wilms Tumor Development

肾母细胞瘤（WT）是一种儿童肾脏肿瘤，是一个非常富有成效的模型，用于了解的作用， 肿瘤发生中的遗传改变和相互作用。WT的病因是遗传异质性的。只 迄今为止，已经鉴定了一种WT基因，WT 1。它只在20%的肾母细胞瘤中发生突变， 在大多数WT家族中易患基因分离。通过我们的工作， 在上一个资助期内，我们首次发现了新的洛缺失区域 以及洛缺失、基因突变和微阵列基因表达谱的模式， 基因定义的肾母细胞瘤亚型。根据这些数据，我们假设， WT的发展涉及多个基因的改变， 共同失调了有限数量的细胞通路，这些通路对细胞的调节至关重要， 肾脏中的增殖和分化。除了WT 1，这些突变基因的身份 并且被废除的同源细胞途径是未知的。即使对于WT 1突变型肿瘤， 细胞通路由于WT 1突变而失调。然而，我们最近关于基因型特异性的数据 基因突变和差异基因表达的模式强烈暗示了几种信号传导 已知在肿瘤发生中起作用的途径。下一个融资期的总体目标是发现 在我们的洛缺失、连锁、突变和表达数据的指导下， 以确定肿瘤发生过程中多个位点/途径的改变如何协同作用。这些 研究还将进一步加深我们对更多生物的分子遗传结构和生物学的理解。 病因复杂的成人肿瘤。由于Wilms肿瘤的生物学途径可能是 常见和独特的儿科肿瘤，我们的工作数据很可能提供额外的见解， 靶向这些途径治疗儿童和成人癌症的方法。 通常控制细胞生长和发育的机制在癌症中被基因突变破坏。 我们将确定这些控制机制是如何在肾母细胞瘤（WT）突变。的机制 在WT中发现的突变也可能是在其他癌症中发现的突变，这项工作将提供 深入了解针对这些机制治疗儿童和成人癌症的方法。

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.