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[Cancer Research 60, 6288-6292, November 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Frequent Association of ß-Catenin and WT1 Mutations in Wilms Tumors1

Sourindra Maiti, Rita Alam, Christopher I. Amos and Vicki Huff2

Department of Biochemistry and Molecular Biology [S. M.], Department of Epidemiology [C. I. A.], and Division of Pediatrics [R. A., V. H.], M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Theetiology of Wilms tumor, an embryonic kidney tumor, is genetically heterogeneous. One Wilms tumor gene, WT1, which encodes a zinc finger transcription factor, is mutated in 10–20% of Wilms tumors, but it is still not clear what critical cellular pathway(s) is affected by these mutations. Recently ß-catenin mutations have been reported in 6 of 40 (15%) of Wilms tumors. ß-catenin is the central effector in the Wnt signal transduction pathway, and deregulation of ß-catenin signaling is critical in the development of a number of malignancies. The observation of ß-catenin mutations in Wilms tumors suggests that abrogation of the Wnt signaling pathway also plays a role in some Wilms tumors. To assess the relationship of WT1 mutations vis-à-vis ß-catenin mutations in Wilms tumor, we analyzed 153 primary tumors, and 21 of 153 (14%) carried ß-catenin mutations. Surprisingly, we observed a highly significant (P = 3.6 x 10-13) association between WT1 and ß-catenin mutations; 19 of 20 ß-catenin-mutant tumors had also sustained WT1 mutations. By analogy to the patterns of concordant and discordant gene mutations observed in other tumors, our data suggest that mutation of WT1 and ß-catenin affects two different cellular pathways, both of which are critically altered in at least a subset of Wilms tumors.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
WT is a pediatric tumor of the kidney. The molecular pathogenesis of WT is poorly understood, but is known to be genetically heterogeneous. The only cloned WT gene, WT1, located on chromosomal band 11p13, was identified by virtue of its association with the WAGR syndrome (1 , 2) . WT1 encodes a zinc finger transcription factor that plays a pivotal role in genitourinary development and acts as a tumor suppressor gene (3, 4, 5) . However, mutational inactivation of WT1 is observed in only 10–20% of Wilms tumors (6, 7, 8) .

The molecular pathways involved in WT development are largely unknown. Many genes have been identified as being putatively regulated by WT1. However, it still is not clear what the biologically critical targets for WT1 regulation are, and the cellular pathways abrogated as a result of WT1 mutations have yet to be identified. The recent identification of ß-catenin mutations in 15% of Wilms tumors, however, implies that alteration of the Wnt signaling pathway is important in the genesis of at least a subset of Wilms tumors (9) .

ß-catenin is a ubiquitous intracellular protein that plays important roles both in intercellular adhesion and in the APC/ß-catenin/Tcf-Lef signaling pathway (10 , 11) . In this pathway, ß-catenin forms a heterodimeric complex with the Tcf/Lef family of DNA binding proteins and regulates transcription of target genes e.g., c-myc and cyclin D1 (12 , 13) . Intracellular turnover of ß-catenin is thought to be regulated by APC and glycogen synthase kinase 3ß-mediated phosphorylation of highly conserved serine and threonine residues in the NH2 terminus region of the protein (10 , 11) . This phosphorylation results in ubiquitination of ß-catenin and targeting of the protein for degradation by the proteasome system (14) . Deletion of the NH2 terminus or mutation of one or more of the serine/threonine residues results in the accumulation of ß-catenin, enhancing its availability as a transcriptional activator (15 , 16) .

Abrogation of the APC/ß-catenin/Tcf-Lef pathway, either by inactivating mutations of the APC gene or by ß-catenin activating mutations that result in reduced serine/threonine phosphorylation, has been recognized as playing a key role in the development of a broad spectrum of malignancies (16, 17, 18, 19, 20, 21, 22, 23) . The observation of ß-catenin mutations in a subset of WT suggests that this pathway is also involved in the genesis of some tumors. Because of the dearth of gene mutations that have been identified in WT and the paucity of knowledge of what cellular pathways are altered in the development of WT, we sought to determine whether mutations at the WT1 and ß-catenin loci were mutually exclusive, mutually present, or randomly occurring with respect to each other. Our data demonstrate a highly significant correlation between the presence of a WT1 mutation and a ß-catenin mutation, suggesting that these genes act in different pathways, both of which are altered in at least a subset of tumors.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Patient Samples.
After informed consent, 153 primary tumors and autologous normal tissue were obtained at surgery from 150 patients. In three cases of patients with bilateral disease, both tumors were analyzed. The integrity of the WT1 locus was assessed for 152 of the 153 tumors, and 39 were identified as carrying WT1 germline and/or somatic mutations. Results of WT1 mutational analyses have been reported previously for 136 of the tumors (6) . Of the 39 WT1 mutant tumors, 32 had sustained deletions or truncating WT1 mutations, 6 tumors carried missense mutations which are thought to abrogate protein function, and 1 tumor carried a mutation that alters splicing. The deletion and truncating mutations occurred throughout the locus. Twenty-one tumors were from patients who had sustained germline WT1 mutations. The frequency of WT1 mutations in this panel of Wilms tumors is greater than the frequency of 21 of 115 (18%) of WT1 mutations we reported previously for tumors from individuals without a family history or congenital anomalies (6) . This is attributable to our current panel consisting of samples from individuals with congenital anomalies (e.g., genitourinary anomalies, anomalies associated with Drash Syndrome, etc.) at a greater frequency than occurs in the WT population.

ß-Catenin Mutational Analyses.
Tumor DNA samples were assessed for mutations in exon 3 of ß-catenin (CTNNB1), the region of the gene in which mutations have been identified in other human tumors (16, 17, 18, 19, 20, 21, 22, 23) . Exon 3 was amplified as described previously (9) with the modification that Taq polymerase (Perkin-Elmer) was used for the PCR reaction. PCR products were assessed for alterations using SSCP analysis as described previously (24) . Aberrant SSCP fragments were verified by an independent PCR/SSCP analysis. Aberrant SSCP fragments were excised from the polyacrylamide gel and reamplified, and the resultant PCR products were sequenced directly. Whenever an alteration was detected in tumor DNA, DNA from autologous normal tissue was also analyzed.

Statistical Analyses.
To test for associations between mutations in ß-catenin and WT1, we used a simple goodness-of-fit test and computed the significance using Fisher’s exact test. To assess the possible biological effect of a ß-catenin mutation in patients, we compared the age at diagnosis of patients whose tumors did or did not carry ß-catenin mutations. As presented below, almost all of the ß-catenin mutant tumors also sustained a WT1 mutation, and germline WT1 mutations are known to result generally in an earlier age of diagnosis. For these reasons, for this analysis we stratified patients on the basis of whether the WT1 mutation was germline or somatic and computed Kaplan-Meier product-limit estimators using the SAS statistical package (25) .


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
We detected ß-catenin mutations in 21 of the 153 tumors (14%; Table 1Citation ). Six different types of ß-catenin mutations were detected and included both in-frame deletions and missense mutations (Table 1Citation and Fig. 1CCitation ). Representative SSCP gel patterns for these six different mutations are shown in Fig. 1ACitation along with representative sequence chromatograms (Fig. 1B)Citation . Seventeen tumors carried mutations that resulted in the loss of the functionally important serine phosphorylation site at residue 45: 10 carried a C348T missense mutation (TCT to TTT) at codon 45; 4 carried a 3-bp deletion (347delTCT) resulting in an in-frame deletion of the serine 45-encoding codon; and 3 tumors carried a different 3-bp deletion (348delCTC) that also results in deletion of serine 45 codon. This latter deletion has not been reported previously. Two other tumors carried another novel ß-catenin mutation: an A to C transversion (A321C) which results in an amino acid substitution at codon 36 (His36Pro). One additional tumor had a missense mutation (C312G) at the codon encoding the highly conserved amino acid 33 in the ubiquitin-dependent proteasomal degradation DSG box replacing the important serine phosphorylation site to cystine. The remaining tumor carried a single nucleotide alteration (A335C) at codon 41, which would change the normal threonine phosphorylation site to a proline residue (Thr41Pro). All of the ß-catenin mutations detected occurred heterozygously in tumor DNA and all were somatic; the ß-catenin mutations detected in the 21 tumors were not present in autologous tissue DNA. This observation that ß-catenin mutations in Wilms tumors are heterozygous and somatic is consistent with what has been observed in other tumor types. In addition, all of the ß-catenin mutations except His36Pro were shown to be present in other tumors.


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  		Table 1 Mutations of ß-catenin gene in tumors from WT patients

 


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  		Fig. 1. A, SSCP analysis of Wilms tumor samples showing normal and aberrant bands. Lanes A, B, C, D, E, and F represent separate tumor samples with the following mutations: A, A321C; B, C348T; C, A335C; D, 347delTCT; E, 348delCTC; and F, C312G. N represents normal kidney samples. B, representative sequence chromatograms of six PCR products which were sequenced directly after PCR-SSCP. C, schematic diagram of ß-catenin exon 3 mutations in Wilms tumor samples. Common serine and threonine residues phosphorylated by glycogen synthase kinase 3ß are underlined. Six different types of mutations found in Wilms tumors are indicated above in bold letters along with the number of times they were observed.

 
Unexpectedly, we found a highly significant association (P = 3.6 x 10-13) between the presence of ß-catenin mutations and the presence of WT1 mutations (Table 2)Citation . Of the 21 tumors harboring a ß-catenin mutation, 19 had also sustained mutations at WT1; 1 tumor carried a ß-catenin mutation in the absence of a detectable WT1 mutation; and 1 tumor carried a ß-catenin mutation, but the status of the WT1 locus is not known. Conversely, of the 38 tumors that carried a WT1 mutation, 19 (50%) were also shown to have sustained a ß-catenin mutation. There was no difference in the location or type (null, truncation, or missense) of the WT1 mutation between the WT1 mutant tumors that did or did not also carry ß-catenin mutations.


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  		Table 2 Association between WT1 mutations and ß-catenin mutationsa

 
ß-catenin mutations occurred in tumors from patients with both unilateral and bilateral disease and with and without congenital anomalies (aniridia, genitourinary anomalies, Drash syndrome). Two patients whose tumors carried ß-catenin mutations were diagnosed with WAGR syndrome and carried large germline deletions encompassing the WT1 and PAX6 genes on 11p13 and additional WT1 tumor-specific mutations (tumors 3 and 16; Table 1Citation ). Another two patients, whose tumors carried somatic ß-catenin mutations, were diagnosed with Drash syndrome and carried WT1 exon 9 germline mutations that were reduced to homozygosity in the tumors (tumors 4 and 14; Table 1Citation ). There was no discernable difference between ß-catenin mutant and ß-catenin nonmutant tumors with respect to tumor histology or stage of disease at diagnosis.

Analysis of the age of WT diagnosis in patients indicated that there was no significant effect on the presence of a ß-catenin mutation. Among the patients who had a germline WT1 mutation, the median age of diagnosis for those also carrying a somatic ß-catenin mutation was 18 months [95% CI = (12, 23)], and for those without a ß-catenin mutation the median age of diagnosis was 25 months [95% CI = (10, 36)]. This difference did not reach statistical significance (P = 0.23). Among patients with somatic WT1 mutations, the median age of diagnosis for those also carrying a somatic ß-catenin mutation was 20.5 months [95% CI = (10, 64)] and for those without a ß-catenin mutation the median age of diagnosis was 29.5 months [95% CI = (20, 124)]. This difference also did not reach statistical significance (P = 0.27), although the same trend toward an earlier age of diagnosis when a ß-catenin mutation is present was observed.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Increasingly, the cellular pathways that are abrogated by genetic alterations in tumors are being identified, and this information has contributed dramatically to understanding the processes of the normal control of cellular growth and differentiation. The genetic analysis of human cancers has additionally resulted in the identification of a few cellular pathways whose normal control mechanisms apparently are invariably circumvented in particular types of cancers. For example, lung carcinomas sustain either RB or p16 mutations (26) , implying that deregulation of the G1 checkpoint, a point in the cell cycle at which the RB and p16 proteins play critical regulatory roles, is necessary for tumorigenesis of lung epithelium, and that this control can be breached by either RB or p16 mutations. Similarly, the Wnt signaling pathway is thought to be deregulated in virtually all colon carcinomas as a result of mutations in one of several genes whose protein products play key roles in the function/regulation of this pathway. The mutually exclusive presence of mutations of APC and ß-catenin, members of the Wnt pathway, implies that alteration of either gene is sufficient to abrogate normal control of cell proliferation. In general, the copresence of genetic alterations known to affect the same pathway are not commonly observed in human tumors. These data further support the notion that alteration in one component of the pathway is sufficient and implies that, in vivo, the deregulation of cellular pathways does not usually occur via the additive accumulation of mutations at multiple genes within a given pathway. Therefore, the observation of genetic alterations that are mutually exclusive in the same tumor suggests that the two affected genetic loci play a role in the same pathway and that alteration of both would be redundant.

In contrast with many adult tumors, for WT, an embryonal kidney tumor derived from mesenchymal cells that normally differentiate into the epithelial components of the kidney, the cellular pathways whose alteration is critical for tumorigenesis are largely unknown. Many genes, some of which are known to play a role in regulation of cell growth or apoptosis, have been identified by in vitro studies as being regulated by WT1, but supporting data from in vivo studies is limited. Examination of WT1 expression patterns in embryos, along with detailed pathological analysis of WT1 null mice, suggest that during organogenesis WT1 is critical for the differentiation of mesenchyme to epithelium in a number of tissues (kidney, spleen, and lung mesothelium; Refs. 4 , 27 , and 28 ), but the genes presumably regulated by WT1 and their cognate cellular pathways that are critical for this differentiation are not known. These observations do, however, suggest that WT1 plays a role in inducing differentiation rather than in the regulation of cell proliferation.

Our identification of ß-catenin mutations in 21 of 153 Wilms tumors (14%) is very similar to that reported recently for a panel of 40 Wilms tumors in which 6 (15%) had sustained a ß-catenin mutation (9) . These data strongly suggest that deregulation of the Wnt signaling pathway, resulting in aberrant control of cellular proliferation, plays a critical role in at least a subset of Wilms tumors. By extension, these data also suggest that the Wnt signaling pathway is involved in regulating cellular growth in the mesenchymal cells from which Wilms tumors arise. The observation that in the developing mouse kidney Wnt-4 is required for the mesenchymal to epithelial transition further supports this notion (29 , 30) .

Unexpectedly, in the current study we identified additionally a highly significant (P = 3.6 x 10-13) association of ß-catenin mutations with WT1 mutations. A similar strong association of mutations in two different genes has been observed also in other tumors. For example, TGFßRII mutations often coexist with ß-catenin mutations in hereditary nonpolyposis colorectal cancer tumors (19) . Because ß-catenin mutations are thought to be sufficient for abrogating control of the Wnt signaling pathway, the concordant presence of TGFßRII mutations suggests that a second critical pathway is affected by the TGFßRII alterations (31 , 32) . Similarly, we propose that in WT, the WT1 and ß-catenin mutations act to alter different cellular pathways, both of which are abrogated in at least a subset of Wilms tumors.

Mutations at the loci encoding different components of the Wnt pathway have been identified in many types of human tumors, most notably colon carcinoma (15 , 17) . The effect of many of these mutations is putative stabilization of ß-catenin, often through the loss of APC function or the mutation of ß-catenin at amino acid residues necessary for its phosphorylation and subsequent degradation. Of the six different types of ß-catenin mutations we detected in Wilms tumors, four have been observed in other cancers and result in amino acid substitutions or deletions at highly conserved serine or threonine phosphorylation sites (Table 2)Citation . This impairment of ß-catenin phosphorylation results in the stabilization of the protein and thus enhances its availability as a transcriptional activator. The 348delCTC mutation, which we observed in three tumors, has not been reported previously, but results in the same deletion of Ser45 that is also the result of a common ß-catenin mutation (347delTCT). Additionally, we detected in two Wilms tumors a novel mutation, A321C His36Pro. This histidine residue is highly conserved in ß-catenin among different species such as Drosophila, Xenopus, and Homo sapiens. Although the functional significance of this mutation is not yet clear, given its location next to a phosphorylation site (Ser37) and the observation of missense mutations in other tumors at amino acids neighboring phosphorylated residues (17 , 23) , we speculate that the His36Pro substitution impairs phosphorylation of ß-catenin.

As with all of the ß-catenin mutations described to date in other tumor types, those we observed in Wilms tumors occurred somatically and were heterozygous, consistent with the model that "activating" mutations at the ß-catenin locus disrupt the normal control of the Wnt signaling pathway. Of interest, in three instances in which we assessed both tumors from patients with bilateral disease, each set of tumors was found to be discordant for ß-catenin mutations. Whether this is attributable, in those tumors which did not carry ß-catenin mutations, to the presence of mutations at other loci in the Wnt pathway is not currently known. Similarly, the gene(s) that is mutated in the 80% of tumors that do not carry a WT1 mutation (nor a ß-catenin mutation) is currently unknown.

Because ß-catenin plays a key role in regulating cellular proliferation, we speculated that the presence of ß-catenin mutations in tumors might result in enhanced cellular proliferation over that observed in tumors without such mutations, and that this enhancement would result in an earlier age of diagnosis. To investigate this possibility, we compared tumors/patients, stratified by whether the concurrent WT1 mutation was somatic or germline, for differences in age at diagnosis. Within each strata, patients whose tumors had sustained ß-catenin mutations were diagnosed at an earlier age than those whose tumors had no detectable ß-catenin mutation. However, these differences did not reach statistical significance (P = 0.23 and P = 0.27, respectively). Assessment of additional patients will be useful for investigating this more thoroughly.

In summary, we have detected a previously unrecognized and highly statistically significant association between ß-catenin mutations and WT1 mutations in Wilms tumors, such that tumors carrying ß-catenin mutations almost invariably carry WT1 mutations. From these data we propose that the two genes alter two different cellular pathways, one of which is the Wnt signaling pathway and each of which is critical in the development of at least a subset of WTs.


   ACKNOWLEDGMENTS
 
We greatly appreciate the cooperation and help of patients and their physicians. We thank P. Begin and D. Sembera for sample collection and Dr. Dakai Zhu for assistance with statistical analyses. We also thank Drs. Cristy Ruteshouser, Pierre McCrea, and Ullrich Mueller for their critical reading of the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by NIH Grants CA78257, CA34936, and CA16672. Back

2 To whom requests for reprints should be addressed, at Division of Pediatrics, Box 88, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030. Phone: (713) 745-0678; Fax: (713) 794-4373; E-mail: vhuff{at}mdacc.tmc.edu Back

3 The abbreviations used are: WT, Wilms tumor; WAGR syndrome, Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation syndrome; APC, adenomatous polyposis coli; SSCP, single-strand conformational polymorphism; RB, retinoblastoma; TGFßRII, transforming growth factor ß receptor II. Back

Received 6/21/00. Accepted 10/ 3/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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R. Fukuzawa, R. W Heathcott, H. E More, and A. E Reeve
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E. Yuan, C.-M. Li, D. J. Yamashiro, J. Kandel, H. Thaker, V. V. Murty, and B. Tycko
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