Molecular Genetic Pathways in Wilms Tumor Development

肾母细胞瘤(Wilms Tumor，WT)是一种儿童肾脏肿瘤，它是一种非常有效的模型，可以用来理解 肿瘤发生中的基因改变和相互作用。WT的病因在遗传上是不同的。仅限 到目前为止，WT基因WT1已经被发现。它只在20%的肾母细胞瘤中发生突变，而不是 在大多数WT家系中易感基因分离。通过我们的工作来表征分子 肾母细胞瘤的解剖在上一个资助期，我们首次发现了新的杂合性缺失区域 以及杂合性缺失、基因突变和微阵列基因表达谱之间的差异 肾母细胞瘤的基因定义亚群。根据这些数据，我们假设限速步骤 WT发生涉及多个基因的改变，不同的突变组合起作用 共同扰乱对细胞调节至关重要的有限数量的细胞通路 肾脏的增殖和分化。除WT1外，这些突变基因的同源性 而被废除的同源细胞通路是未知的。即使对于WT1突变的肿瘤，也不清楚是什么 WT1基因突变导致细胞通路失调。然而，我们最近关于特定基因型的数据 基因突变和差异基因表达的模式强烈地暗示了几个信号 已知的在肿瘤发生中发挥作用的途径。下一个资助期的总体目标是发现 在我们的杂合性缺失、连锁、突变和表达数据的指导下，调查-WT“途径”表型 并确定在肿瘤发生过程中多个基因位点/通路的改变如何协同作用。这些 研究还将进一步加深我们对More的分子遗传结构和生物学的理解 病因复杂的成人肿瘤。因为发现的肾母细胞瘤的生物学途径可能既有 儿科肿瘤常见而独特，我们的工作数据很可能为我们提供更多关于 针对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Wilms瘤(WT)中突变的。其作用机制 被确认为WT的人也可能是那些在其他癌症中突变的人，拟议的工作将提供 洞察针对儿童和成人癌症治疗的这些机制的方法。

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.