Mutational activation of the β-catenin proto-oncogene is a common event in the development of Wilms' tumors

Department of Surgery, University of Heidelberg, Germany.
Cancer Research (Impact Factor: 9.33). 09/1999; 59(16):3880-2.
Source: PubMed


Activation of beta-catenin-mediated transcription is the nuclear end point of organ-specific Wnt signaling. In the developing kidney, Wnt-4, a secreted glycoprotein, acts as an autoinducer of the mesenchymal to epithelial transition that underlies normal nephron development. Dysregulation of this epithelial transformation process may lead to Wilms' tumors (WTs). In this study, we investigated the potential role of the beta-catenin proto-oncogene, a candidate downstream target molecule of Wnt-4 signaling, in the development of WTs. In 6 of 40 tumors (15%), mutation analysis revealed heterozygous missense mutations or small deletions that result in the loss of important regulatory phosphorylation sites within the beta-catenin protein. These findings indicate that activating beta-catenin mutations may play a significant role in the development of WTs and establish a direct link between Wilms' tumorigenesis and the Wnt signal transduction pathway governing normal kidney development.

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    • "This led to the identification of the WT1 tumour suppressor gene, loss of which is the rate-limiting step in 15% of Wilms' tumours (Hohenstein et al., 2015). This subset of cases is characterized by ectopic muscle development (Miyagawa et al., 1998; Schumacher et al., 2003) and selection for activating mutations in CTNNB1, the gene encoding β-catenin (Koesters et al., 1999; Maiti et al., 2000). Accordingly, the WT1 wild-type and mutant subsets of tumours can clearly be recognized using genome-wide expression analysis (Corbin et al., 2009; Gadd et al., 2012; Li et al., 2004). "
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    ABSTRACT: Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal to epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models to human tumour material of WT1-mutant and WT1 wild-type datasets identifies the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin. © 2015. Published by The Company of Biologists Ltd.
    Disease Models and Mechanisms 05/2015; 142(16). DOI:10.1242/dmm.018523 · 4.97 Impact Factor
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    • "The next Wilms' tumor gene identified, also with a role in renal development, was CTNNB1, which is mutated somatically in 15% of tumors, often alongside a WT1 mutation (Koesters et al. 1999; Maiti et al. 2000). CTNNB1 encodes b-catenin, a key protein involved in the Wnt signaling pathway, which is critical for epithelialization after MET (Koesters et al. 1999). In Wilms' tumor, the CTNNB1 mutation commonly occurs at a specific activating residue (Ser45) (Kusafuka et al. 2002), causing nuclear accumulation of b-catenin (Koesters et al. 2003). "
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    ABSTRACT: Wilms' tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms' tumor in the context of renal development. Many of the genes implicated in Wilms' tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general-and specific miRNAs in particular-in normal kidney development that still await further analysis. The recent identification of Wilms' tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions. © 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 03/2015; 29(5):467-482. DOI:10.1101/gad.256396.114 · 10.80 Impact Factor
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    • "Interestingly, the sustained activation of β-catenin blocks MET, suggesting that β-catenin-mediated signaling has to be inhibited to complete the nephron development. Activating β-catenin mutations have been reported in Wilms tumors, which typically show an incompletely epithelialized blastemal component indicating a failure during early nephron differentiation [39, 40]. "
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    ABSTRACT: Several Wnt proteins are expressed in the embryonic kidney during various stages of development. Gene knockout models and ex vivo studies have provided strong evidence that Wnt-mediated signals are essential in renal ontogeny. Perhaps the most critical factors, Wnt9b and Wnt4, function during the early phase when the cap mesenchyme is induced to undergo morphogenesis into a nephron. Wnt11 controls early ureteric bud branching and contributes to the final kidney size. In addition to its inductive role, later on Wnt9b plays a significant role in the convergent extension of the tubular epithelial cells, while Wnt4 signaling controls smooth muscle cell fates in the medulla. Wnt7b has a specific function together with its likely antagonist Dkk1 in controlling the morphogenesis of the renal medulla. The signal-transduction mechanisms of the Wnts in kidney ontogeny have not been resolved, but studies characterizing the downstream signaling pathways are emerging. Aberrant Wnt signaling may lead to kidney diseases ranging from fatal kidney agenesis to more benign phenotypes. Wnt-mediated signaling regulates several critical aspects of kidney development from the early inductive stages to later steps of tubular epithelial maturation.
    Pediatric Nephrology 01/2014; 29(4). DOI:10.1007/s00467-013-2733-z · 2.86 Impact Factor
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