Gene Summary

Gene:AMER1; APC membrane recruitment protein 1
Aliases: WTX, OSCS, FAM123B
Summary:The protein encoded by this gene upregulates trancriptional activation by the Wilms tumor protein and interacts with many other proteins, including CTNNB1, APC, AXIN1, and AXIN2. Defects in this gene are a cause of osteopathia striata with cranial sclerosis (OSCS). [provided by RefSeq, May 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:APC membrane recruitment protein 1
Source:NCBIAccessed: 17 March, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 March 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Adenomatous Polyposis Coli Protein
  • siRNA
  • Cytoplasm
  • Base Sequence
  • Chromosome 11
  • Loss of Heterozygosity
  • Cell Proliferation
  • Kidney
  • X Chromosome
  • Neoplastic Cell Transformation
  • Kidney Cancer
  • Gene Deletion
  • Childhood Cancer
  • Wilms Tumor Genes
  • Point Mutation
  • Immunohistochemistry
  • Signal Transducing Adaptor Proteins
  • DNA Methylation
  • Cell Nucleus
  • Genetic Predisposition
  • Signal Transduction
  • Single Nucleotide Polymorphism
  • beta Catenin
  • Wnt Proteins
  • Gene Expression Profiling
  • Chromosome X
  • DNA Mutational Analysis
  • Stomach Cancer
  • WT1
  • Nuclear Proteins
  • Cancer Gene Expression Regulation
  • AMER1 (WTX)
  • Adolescents
  • Wilms Tumour
  • X Chromosome Inactivation
  • Cell Line
  • Wnt Signaling Pathway
  • Polymerase Chain Reaction
  • Infant
  • Tumor Suppressor Proteins
  • Mutation
Tag cloud generated 17 March, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: AMER1 (cancer-related)

Tian F, Yourek G, Shi X, Yang Y
The development of Wilms tumor: from WT1 and microRNA to animal models.
Biochim Biophys Acta. 2014; 1846(1):180-7 [PubMed] Related Publications
Wilms tumor recapitulates the development of the kidney and represents a unique opportunity to understand the relationship between normal and tumor development. This has been illustrated by the findings that mutations of Wnt/β-catenin pathway-related WT1, β-catenin, and WTX together account for about one-third of Wilms tumor cases. While intense efforts are being made to explore the genetic basis of the other two-thirds of tumor cases, it is worth noting that, epigenetic changes, particularly the loss of imprinting of the DNA region encoding the major fetal growth factor IGF2, which results in its biallelic over-expression, are closely associated with the development of many Wilms tumors. Recent investigations also revealed that mutations of Drosha and Dicer, the RNases required for miRNA generation, and Dis3L2, the 3'-5' exonuclease that normally degrades miRNAs and mRNAs, could cause predisposition to Wilms tumors, demonstrating that miRNA can play a pivotal role in Wilms tumor development. Interestingly, Lin28, a direct target of miRNA let-7 and potent regulator of stem cell self-renewal and differentiation, is significantly elevated in some Wilms tumors, and enforced expression of Lin28 during kidney development could induce Wilms tumor. With the success in establishing mice nephroblastoma models through over-expressing IGF2 and deleting WT1, and advances in understanding the ENU-induced rat model, we are now able to explore the molecular and cellular mechanisms induced by these genetic, epigenetic, and miRNA alterations in animal models to understand the development of Wilms tumor. These animal models may also serve as valuable systems to assess new treatment targets and strategies for Wilms tumor.

Al-Hussain T, Ali A, Akhtar M
Wilms tumor: an update.
Adv Anat Pathol. 2014; 21(3):166-73 [PubMed] Related Publications
Wilms tumor (WT) is the most common neoplasm of the kidney in children. It is an embryologic tumor that histologically mimics renal embryogenesis and is composed of a variable mixture of stromal, blastemal, and epithelial elements. Nephrogenic rests, generally considered to be precursor lesions of the WT, are foci of the embryonic metanephric tissue that persist after the completion of renal embryogenesis. These are classified as perilobar and intralobar based on their location and maybe present as single or multiple foci. Intralobar and perilobar rests and the tumors arising from these rests differ morphologically and are characterized by 2 different sets of genetic abnormalities involving 2 adjacent foci, WT1 and WT2, on the short arm of chromosome 11. WTs arising in the intralobar rests tend to be stromal predominant and have a mutation or deletion of WT1. Germline mutation in WT1 may be associated with syndromic conditions such as WAGR and Denys-Drash syndromes. Perilobar rests and their corresponding tumors usually have loss of imprinting/loss of heterozygosity involving WT2, which contains several parentally imprinted genes. Loss of function of these genes, if present constitutionally, may be associated with Beckwith-Wiedemann syndrome or may result in isolated hypertrophy. Abnormalities in several other genes may also be seen in WT. These include WTX, (on chromosome X), CTNNB1 (chromosome 3), and TP53 (chromosome 17) among others. WT with loss of heterozygosity at 1p and 16q may have poor prognosis, requiring aggressive therapy. Treatment modalities for WT have evolved over many decades, primarily through the efforts of Dr J Bruce Beckwith at National WT study. This work is now being carried out by Children Oncology Group in North America and International Society of Pediatric Oncology in Europe. Although their therapeutic approaches are somewhat different, both have reported excellent results with equally high cure rates.

Nishida S, Koido S, Takeda Y, et al.
Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer.
J Immunother. 2014 Feb-Mar; 37(2):105-14 [PubMed] Free Access to Full Article Related Publications
Wilms tumor gene (WT1) protein is an attractive target for cancer immunotherapy. We aimed to investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide-based vaccine for patients with advanced pancreatic cancer and to make initial assessments of its clinical efficacy and immunologic response. Thirty-two HLA-A*24:02 patients with advanced pancreatic cancer were enrolled. Patients received HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg/body) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) intradermally biweekly and gemcitabine (1000 mg/m) on days 1, 8, and 15 of a 28-day cycle. This combination therapy was well tolerated. The frequencies of grade 3-4 adverse events for this combination therapy were similar to those for gemcitabine alone. Objective response rate was 20.0% (6/30 evaluable patients). Median survival time and 1-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity to WT1 peptide was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes both before and after treatment. WT1 vaccine in combination with gemcitabine was well tolerated for patients with advanced pancreatic cancer. Delayed-type hypersensitivity-positivity to WT1 peptide and a higher frequency of memory-phenotype WT1-specific cytotoxic T lymphocytes could be useful prognostic markers for survival in the combination therapy with gemcitabine and WT1 vaccine. Further clinical investigation is warranted to determine the effectiveness of this combination therapy.

Fujita A, Ochi N, Fujimaki H, et al.
A novel WTX mutation in a female patient with osteopathia striata with cranial sclerosis and hepatoblastoma.
Am J Med Genet A. 2014; 164A(4):998-1002 [PubMed] Related Publications
Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant sclerosing bone dysplasia. Typically affected females show macrocephaly, characteristic facial appearance, cleft palate, mild learning difficulties, hearing loss, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis and scapulae. Typically affected males usually die at the fetal or early neonatal stage. Because of its variable expressivity, which ranges from asymptomatic to fetal death, clinical diagnosis of OSCS can be difficult. Here, we identify a unique female patient presenting with severe macrocephaly, characteristic facial appearance, developmental delay, and hepatoblastoma. Exome sequencing identified a novel de novo nonsense mutation (c.1045C>T, p.Glu349*) in the WTX gene associated with OSCS. The OSCS diagnosis was confirmed in this patient based on the hallmark appearance of longitudinal striations in long bones when viewed by X-ray. WTX is also known as a tumor suppressor gene, and somatic mutations in that gene have been identified in Wilms tumors. In addition to this patient, although two patients with OSCS have been reported to have colorectal cancer or ovarian cancer, Wilms tumor has never been reported in association with this disorder. Tumor susceptibility in patients with OSCS is discussed.

Brauburger K, Akyildiz S, Ruppert JG, et al.
Adenomatous polyposis coli (APC) membrane recruitment 3, a member of the APC membrane recruitment family of APC-binding proteins, is a positive regulator of Wnt-β-catenin signalling.
FEBS J. 2014; 281(3):787-801 [PubMed] Related Publications
The adenomatous polyposis coli (APC) membrane recruitment (Amer) family proteins Amer1/Wilms tumour gene on the X chromosome and Amer2 are binding partners of the APC tumour suppressor protein, and act as negative regulators in the Wnt signalling cascade. So far, nothing has been known about the third member of the family, Amer3. Here we show that Amer3 binds to the armadillo repeat domain of APC, similarly to Amer1 and Amer2. Amer3 also binds to the Wnt pathway regulator conductin/axin2. Furthermore, we identified Amer1 as binding partner of Amer3. Whereas Amer1 and Amer2 are linked to the plasma membrane by an N-terminal membrane localization domain, Amer3 lacks this domain. Amer3 localizes to the cytoplasm and nucleus of epithelial cells, and this is dependent on specific nuclear import and export sequences. Functionally, exogenous Amer3 enhances the expression of a β-catenin/T-cell factor-dependent reporter gene, and knockdown of endogenous Amer3 reduces Wnt target gene expression in colorectal cancer cells. Thus, Amer3 acts as an activator of Wnt signalling, in contrast to Amer1 and Amer2, which are inhibitors, suggesting a nonredundant role of Amer proteins in the regulation of this pathway. Our data, together with those of previous studies, provide a comprehensive picture of similarities and differences within the Amer protein family.

Akhavanfard S, Vargas SO, Han M, et al.
Inactivation of the tumor suppressor WTX in a subset of pediatric tumors.
Genes Chromosomes Cancer. 2014; 53(1):67-77 [PubMed] Related Publications
WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.

Liu Y, Liu S
Berberine inhibits Wilms' tumor cell progression through upregulation of Wilms' tumor gene on the X chromosome.
Mol Med Rep. 2013; 8(5):1537-41 [PubMed] Related Publications
Wilms' tumor is a type of kidney cancer that affects young children. Although a number of Wilms' tumor samples have been collected through international trials, the mechanisms underlying its progression remain challenging to determine. Extensive studies have identified somatic mutations at several loci in Wilms' tumorigenesis, including WT1, catenin, Wilms' tumor gene on the X chromosome (WTX) and TP53. Berberine is a benzylisoquinoline alkaloid extracted from numerous types of medicinal plants and has been extensively used as a Chinese traditional medicine. Recently, berberine has been demonstrated to possess antitumoral activities. AMP-activated protein kinase (AMPK) is suggested to be one of the various cellular targets of berberine, which regulates tumor progression and metastasis. However, the specific involvement of berberine‑induced AMPK activation and its effects on the proliferation potential of Wilms' tumor cells remains unknown. The present study investigated the berberine‑induced activation of AMPK and its effects on G401 Wilms' tumor cell proliferation. The results demonstrated that berberine inhibited growth and decreased the expression of cell‑cycle regulators in these cells. At the molecular level, berberine treatment led to a significant increase of WTX expression and G401 cells were protected against berberine‑induced growth inhibition by small interfering RNA against WTX. In conclusion, these results suggest a novel mechanism that may contribute to the antineoplastic effects of berberine which was also demonstrated by recent population studies; however, further studies are required to investigate the potential therapeutic use of berberine in patients with Wilms' tumor.

Liu X, Wang Q, Niu H, et al.
Promoter methylation of Wilms' tumor gene on the X- chromosome in gastric cancer.
Nan Fang Yi Ke Da Xue Xue Bao. 2013; 33(3):318-21 [PubMed] Related Publications
OBJECTIVE: To investigate the changes in methylation levels of the promoters of the tumor suppressor gene Wilms' tumor gene on the X-chromosome (WTX) and its possible role in gastric cancer.
METHODS: WTX promoter methylation levels were detected in 20 pairs of specimens of gastric cancer and matched normal tissues and in 3 gastric cancer cell lines (MGC803, SCG7901, and BGC823) using the Sequenom MassARRAY quantitative analysis system. The gastric cancer cell line BGC823 was treated with 5-aza-2'-deoxycytidine (5-aza-dC) for demethylation and the changes in the level of WTX promoter methylation were investigated.
RESULTS: WTX promoter methylation levels were very low and showed no significant differences among normal gastric tissues, gastric cancer tissues and the 3 gastric cancer cell lines. In BGC823 cells, treatment with 5-aza-dC did not obviously affect the promoter methylation levels of WTX.
CONCLUSION: High methylation levels of WTX promoters are rare in gastric cancer.

Segers H, van den Heuvel-Eibrink MM, de Krijger RR, et al.
Defects in the DNA mismatch repair system do not contribute to the development of childhood wilms tumors.
Pediatr Dev Pathol. 2013 Jan-Feb; 16(1):14-9 [PubMed] Related Publications
Wilms tumor is the most common childhood renal malignancy. Most Wilms tumors occur sporadically, whereas a genetic predisposition is described in 9-19% of the Wilms tumor patients. In addition to constitutional aberrations, somatic aberrations in multiple genetic loci such as WT1, WT2 or locus 11p15.5, CTNNB1, WTX, TP53, FBXW7, and MYCN have also been linked to Wilms tumorigenesis. In sporadic Wilms tumors, however, the driving somatic genetic aberrations need to be further unraveled. Therefore, it is necessary to obtain more insight into other underlying mechanisms. Little is known about the role of defects in the DNA mismatch repair system in the etiology of Wilms tumors. To detect mismatch repair deficiency in a full cohort of Wilms tumor patients, we combined immunohistochemistry for the expression of mismatch repair proteins and microsatellite instability (MSI) analysis by a fluorescent multiplex polymerase chain reaction-based assay. Of the 121 Wilms tumor patients treated between 1987 and 2010 in our institution, 100 samples from 97 patients were available for analysis. Nuclear staining for MLH1, MSH2, MSH6, and PMS2 proteins was present in all 100 Wilms tumor samples. No pattern of MSI was found in any of the 100 investigated Wilms tumor samples. The matching results of normal expression of the mismatch repair proteins detected by immunohistochemistry and the absence of MSI by DNA analysis in 100 Wilms tumor samples lead us to conclude that defects in the DNA mismatch repair system do not play a significant role in the development of Wilms tumors.

Hast BE, Goldfarb D, Mulvaney KM, et al.
Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination.
Cancer Res. 2013; 73(7):2199-210 [PubMed] Free Access to Full Article Related Publications
Somatic mutations in the KEAP1 ubiquitin ligase or its substrate NRF2 (NFE2L2) commonly occur in human cancer, resulting in constitutive NRF2-mediated transcription of cytoprotective genes. However, many tumors display high NRF2 activity in the absence of mutation, supporting the hypothesis that alternative mechanisms of pathway activation exist. Previously, we and others discovered that via a competitive binding mechanism, the proteins WTX (AMER1), PALB2, and SQSTM1 bind KEAP1 to activate NRF2. Proteomic analysis of the KEAP1 protein interaction network revealed a significant enrichment of associated proteins containing an ETGE amino acid motif, which matches the KEAP1 interaction motif found in NRF2. Like WTX, PALB2, and SQSTM1, we found that the dipeptidyl peptidase 3 (DPP3) protein binds KEAP1 via an "ETGE" motif to displace NRF2, thus inhibiting NRF2 ubiquitination and driving NRF2-dependent transcription. Comparing the spectrum of KEAP1-interacting proteins with the genomic profile of 178 squamous cell lung carcinomas characterized by The Cancer Genome Atlas revealed amplification and mRNA overexpression of the DPP3 gene in tumors with high NRF2 activity but lacking NRF2 stabilizing mutations. We further show that tumor-derived mutations in KEAP1 are hypomorphic with respect to NRF2 inhibition and that DPP3 overexpression in the presence of these mutants further promotes NRF2 activation. Collectively, our findings further support the competition model of NRF2 activation and suggest that "ETGE"-containing proteins such as DPP3 contribute to NRF2 activity in cancer.

Cao X, Liu D, Yan X, et al.
Stat3 inhibits WTX expression through up-regulation of microRNA-370 in Wilms tumor.
FEBS Lett. 2013; 587(6):639-44 [PubMed] Related Publications
Wilms tumor (WT) is a genetically heterogeneous childhood kidney tumor. Several genetic mutations have been identified in WT patients, including inactivation of WTX, somatic stabilizing CTNNB1, and p53 mutations. However, the molecular mechanisms in tumorigenesis remain largely unexplored. Stat3 is a transcription factor that can promote oncogenesis. Stat3 activation is commonly viewed as crucial for multiple tumor proliferation and metastasis. We show that Stat3 is highly activated in Wilms tumor tissues compared to those in adjacent tissues. IL-6 treatment or transfection of a constitutively activated Stat3 in G401 cells promotes cell proliferation. At the molecular level, we further elucidate that Stat3 inhibits WTX expression through up-regulation of microRNA-370. Our results suggest that Stat3/miR-370/WTX regulatory axis might be a critical mechanism in Wilms tumor cells.

Cardoso LC, De Souza KR, De O Reis AH, et al.
WT1, WTX and CTNNB1 mutation analysis in 43 patients with sporadic Wilms' tumor.
Oncol Rep. 2013; 29(1):315-20 [PubMed] Related Publications
Wilms' tumor (WT) is a heterogeneous neoplasia characterized by a number of genetic abnormalities, involving tumor suppressor genes, oncogenes and genes related to the Wnt signaling pathway. Somatic biallelic inactivation of WT1 is observed in 5-10% of sporadic WT. Somatic mutations in exon 3 of CTNNB1, which encodes β-catenin, were initially observed in 15% of WT. WTX encodes a protein that negatively regulates the Wnt/β-catenin signaling pathway and mediates the binding of WT1. In this study, we screened germline and somatic mutations in selected regions of WT1, WTX and CTNNB1 in 43 WT patients. Mutation analysis of WT1 identified two single-nucleotide polymorphisms, one recurrent nonsense mutation (p.R458X) in a patient with proteinuria but without genitourinary findings of Denys-Drash syndrome (DDS) and one novel missense mutation, p.C428Y, in a patient with Denys-Drash syndrome phenotype. WT1 SNP rs16754A>G (R369R) was observed in 17/43 patients, and was not associated with significant difference in age at diagnosis distribution, or with 60-month overall survival rate. WTX mutation analysis identified five sequence variations, two synonymous substitutions (p.Q1019Q and p.D379D), a non-synonymous mutation (p.F159L), one frameshift mutation (p.157X) and a novel missense mutation, p.R560W. Two sequence variations in CTNNB1 were identified, p.T41A and p.S45C. Overall survival of bilateral cases was significantly lower (p=0.005). No difference was observed when survival was analyzed among patients with WT1 or with WTX mutations. On the other hand, the survival of two patients with the CTNNB1 p.T41A mutation was significantly lower (p=0.000517) than the average.

Gadd S, Huff V, Huang CC, et al.
Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor: a Children's Oncology Group Study.
Neoplasia. 2012; 14(8):742-56 [PubMed] Free Access to Full Article Related Publications
Wilms tumors (WT) have provided broad insights into the interface between development and tumorigenesis. Further understanding is confounded by their genetic, histologic, and clinical heterogeneity, the basis of which remains largely unknown. We evaluated 224 WT for global gene expression patterns; WT1, CTNNB1, and WTX mutation; and 11p15 copy number and methylation patterns. Five subsets were identified showing distinct differences in their pathologic and clinical features: these findings were validated in 100 additional WT. The gene expression pattern of each subset was compared with published gene expression profiles during normal renal development. A novel subset of epithelial WT in infants lacked WT1, CTNNB1, and WTX mutations and nephrogenic rests and displayed a gene expression pattern of the postinduction nephron, and none recurred. Three subsets were characterized by a low expression of WT1 and intralobar nephrogenic rests. These differed in their frequency of WT1 and CTNNB1 mutations, in their age, in their relapse rate, and in their expression similarities with the intermediate mesoderm versus the metanephric mesenchyme. The largest subset was characterized by biallelic methylation of the imprint control region 1, a gene expression profile of the metanephric mesenchyme, and both interlunar and perilobar nephrogenic rests. These data provide a biologic explanation for the clinical and pathologic heterogeneity seen within WT and enable the future development of subset-specific therapeutic strategies. Further, these data support a revision of the current model of WT ontogeny, which allows for an interplay between the type of initiating event and the developmental stage in which it occurs.

Comprehensive molecular characterization of human colon and rectal cancer.
Nature. 2012; 487(7407):330-7 [PubMed] Free Access to Full Article Related Publications
To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.

Wang H, Shen Y, Sun N, et al.
Identification and analysis of mutations in WTX and WT1 genes in peripheral blood and tumor tissue of children with Wilms' tumor.
Chin Med J (Engl). 2012; 125(10):1733-9 [PubMed] Related Publications
BACKGROUND: Wilms' tumor (nephroblastoma) is the most common pediatric kidney cancer. Only one Wilms' tumor gene is known, WT1 at 11p13, which is mutated in 5% - 10% of Wilms' tumors. Recently, mutations were reported in WTX at Xq11.1 in Wilms' tumors. This study investigated the mutation proportion, type, and distribution in WTX and WT1 in children with Wilms' tumor. The role of WTX/WT1 in the development of Wilms' tumor, and the relationship between clinical phenotype and genotype, were also studied.
METHODS: Wilms' tumor specimens (blood samples from 70 patients and tumor tissue samples from 52 patients) were used. A long fragment of WTX and 10 exons and intron sequences of WT1 were amplified by polymerase chain reaction (PCR) from extracted genomic DNA and sequenced. A chi-square test compared the difference between the WTX mutation group and the no mutation group. The relationship between the mutations and clinical phenotype was analyzed.
RESULTS: WTX mutations were found in 5/52 tumor tissues and in 2/70 peripheral blood samples (five cases in total, all point mutations). Two patients had a WTX mutation in both samples. WT1 mutations were found in 2/52 tumor tissues and in 4/70 peripheral blood samples (five cases in total, all point mutations). One patient had a WT1 mutation in both samples. Ten cases had WTX or WT1 mutation (19.2% of Wilms' tumors). No overlapping WTX and WT1 mutations were found. No significant differences in clinical parameters were found between patients with and without a WTX mutation.
CONCLUSIONS: WTX mutations occur early in Wilms' tumor development, but at a low proportion. There was no evidence that WTX is the main cause of Wilms' tumor. Clinical parameters of patients with WTX mutations are not related to the mutation, indicating a limited impact of WTX on tumor progression. WTX and WT1 mutations occur independently, suggesting a relationship between their gene products.

Brown KW, Charles A, Dallosso A, et al.
Characterization of 17.94, a novel anaplastic Wilms' tumor cell line.
Cancer Genet. 2012; 205(6):319-26 [PubMed] Related Publications
Despite considerable advances in understanding the molecular pathogenesis of Wilms' tumor (WT), its cell biology is less well understood, partly due to the paucity of established WT cell lines. We report here the establishment of a new anaplastic WT cell line, 17.94, which expressed NCAM, SALL1, and CITED1-phenotypic features expected of metanephric blastema-derived cells. Treatment of 17.94 cells with 12-O-Tetradecanoylphorbol 13-acetate caused morphological changes, which led to reduced NCAM and SALL1 expression, but expression of vimentin was maintained, indicating a potential for stromal differentiation. The 17.94 cell line contained a TP53 mutation, consistent with the anaplastic histology of the original tumor, but lacked mutations in WT1, WTX, or CTNNB1, which are the other genes involved in WT pathogenesis. The 17.94 cells showed no loss of heterozygosity at 7p, 11p, or 16q; however, DNA hypermethylation was detected at several loci, including the H19 differentially methylated region (indicative of loss of imprinting of IGF2 at 11p15) and at the PCDH@ gene clusters at 5q31. The derivation of the 17.94 cell line should help to further dissect the genetic-epigenetic interactions involved in the pathogenesis of WT.

Scott RH, Murray A, Baskcomb L, et al.
Stratification of Wilms tumor by genetic and epigenetic analysis.
Oncotarget. 2012; 3(3):327-35 [PubMed] Free Access to Full Article Related Publications
Somatic defects at five loci, WT1, CTNNB1, WTX, TP53 and the imprinted 11p15 region, are implicated in Wilms tumor, the commonest childhood kidney cancer. In this study we analysed all five loci in 120 Wilms tumors. We identified epigenetic 11p15 abnormalities in 69% of tumors, 37% were H19 epimutations and 32% were paternal uniparental disomy (pUPD). We identified mutations of WTX in 32%, CTNNB1 in 15%, WT1 in 12% and TP53 in 5% of tumors. We identified several significant associations: between 11p15 and WTX (P=0.007), between WT1 and CTNNB1 (P less than 0.001), between WT1 and pUPD 11p15 (P=0.01), and a strong negative association between WT1 and H19 epimutation (P less than 0.001). We next used these data to stratify Wilms tumor into three molecular Groups, based on the status at 11p15 and WT1. Group 1 tumors (63%) were defined as 11p15-mutant and WT1-normal; a third also had WTX mutations. Group 2 tumors (13%) were WT1-mutant. They either had 11p15 pUPD or were 11p15-normal. Almost all had CTNNB1 mutations but none had H19 epimutation. Group 3 tumors (25%) were defined as 11p15-normal and WT1-normal and were typically normal at all five loci (P less than 0.001). We also identified a novel clinical association between H19 epimutation and bilateral disease (P less than 0.001). These data provide new insights into the pattern, order, interactions and clinical associations of molecular events in Wilms tumor.

Royer-Pokora B
Genetics of pediatric renal tumors.
Pediatr Nephrol. 2013; 28(1):13-23 [PubMed] Related Publications
Wilms tumor (WT) accounts for approximately 95 % of all pediatric renal tumors, with a peak incidence between 2 and 3 years of age. It occurs in sporadic and congenital forms, the latter often occurring before 1 year of age. Incidence declines with age, and WT rarely is observed in adults. WT is an embryonal tumor of the kidney caused by aberrant proliferation of early metanephric kidney cells. It can arise from more than one developmental error and therefore several subtypes can be defined. WT1, a zinc-finger transcription factor, was identified as the first WT gene. Other genes frequently altered somatically in subsets of WT are CTNNB1 and WTX; both genes influence the Wnt signalling pathway. Imprinting alterations of genes in 11p15 are also observed in a subset of WTs. Other pediatric renal tumors occur less often, e.g. malignant rhabdoid tumor of the kidney, clear-cell sarcoma, desmoplastic small-round-cell tumors, congenital mesoblastic nephroma, renal cell carcinoma of childhood, renal primitive neuroectodermal tumors, renal medullary carcinoma, and synovial sarcoma of the kidney. In most of these, characteristic genetic alterations have been identified that help in the unequivocal diagnosis of these childhood renal cancers that are often difficult to distinguish.

Haruta M, Arai Y, Watanabe N, et al.
Different incidences of epigenetic but not genetic abnormalities between Wilms tumors in Japanese and Caucasian children.
Cancer Sci. 2012; 103(6):1129-35 [PubMed] Related Publications
Epidemiological studies show that the incidence of Wilms tumor (WT) in East-Asian children is half of that in Caucasian children. Abnormalities of WT1, CTNNB1, WTX, and IGF2 were reported to be involved in Wilms tumorigenesis in Caucasians, although none of the studies simultaneously evaluated the four genes. WTX forms the β-catenin degradation complex; however, the relationship between WTX abnormality and CTNNB1 mutation was uncertain in WTs. We examined abnormalities of the four genes in 114 Japanese with WTs to clarify the relationship between genetic and epigenetic factors and the incidence of WTs. We found that abnormalities of WTX and CTNNB1 were mutually exclusive, and that although CTNNB1 mutation was frequent in WTs with WT1 abnormality, but rare in WTs without, the incidences of WTX abnormality were similar between WTs with or without WT1 abnormality. These findings were consistent with those reported in Caucasian populations, and indicate multiple roles of WTX abnormality. Abnormalities of WT1, WTX and CTNNB1, and loss of IGF2 imprinting (LOI) were detected in 31.6%, 22.8%, 26.3%, and 21.1% of the 114 WTs, respectively. When we selected 101 sporadic WTs, the incidences of WT1, CTNNB1, or WTX abnormality were generally comparable between the two populations, whereas the incidence of IGF2 LOI was lower in Japanese than that of IGF2 LOI reported in Caucasians (P = 0.04). This is the first comprehensive study of the four genes, and the results supported the hypothesis that the lower incidence of IGF2 LOI contributes to the lower incidence of WTs in Japanese children.

Camp ND, James RG, Dawson DW, et al.
Wilms tumor gene on X chromosome (WTX) inhibits degradation of NRF2 protein through competitive binding to KEAP1 protein.
J Biol Chem. 2012; 287(9):6539-50 [PubMed] Free Access to Full Article Related Publications
WTX is a tumor suppressor protein that is lost or mutated in up to 30% of cases of Wilms tumor. Among its known functions, WTX interacts with the β-transducin repeat containing family of ubiquitin ligase adaptors and promotes the ubiquitination and degradation of the transcription factor β-catenin, a key control point in the WNT/β-catenin signaling pathway. Here, we report that WTX interacts with a second ubiquitin ligase adaptor, KEAP1, which functions to regulate the ubiquitination of the transcription factor NRF2, a key control point in the antioxidant response. Surprisingly, we find that unlike its ability to promote the ubiquitination of β-catenin, WTX inhibits the ubiquitination of NRF2. WTX and NRF2 compete for binding to KEAP1, and thus loss of WTX leads to rapid ubiquitination and degradation of NRF2 and a reduced response to cytotoxic insult. These results expand our understanding of the molecular mechanisms of WTX and reveal a novel regulatory mechanism governing the antioxidant response.

Clark PE, Polosukhina D, Love H, et al.
β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms' tumors.
Am J Pathol. 2011; 179(6):3045-55 [PubMed] Free Access to Full Article Related Publications
Wilms' tumor (WT) is the most common childhood renal cancer. Although mutations in known tumor-associated genes (WT1, WTX, and CATNB) occur only in a third of tumors, many tumors show evidence of activated β-catenin-dependent Wnt signaling, but the molecular mechanism by which this occurs is unknown. A key obstacle to understanding the pathogenesis of WT is the paucity of mouse models that recapitulate its features in humans. Herein, we describe a transgenic mouse model of primitive renal epithelial neoplasms that have high penetrance and mimic the epithelial component of human WT. Introduction of a stabilizing β-catenin mutation restricted to the kidney is sufficient to induce primitive renal epithelial tumors; however, when compounded with activation of K-RAS, the mice develop large, bilateral, metastatic, multifocal primitive renal epithelial tumors that have the histologic and staining characteristics of the epithelial component of human WT. These highly malignant tumors have increased activation of the phosphatidylinositol 3-kinase-AKT and extracellular signal-regulated kinase pathways, increased expression of total and nuclear β-catenin, and increased downstream targets of this pathway, such as c-Myc and survivin. Thus, we developed a novel mouse model in which activated K-RAS synergizes with canonical Wnt/β-catenin signaling to form metastatic primitive renal epithelial tumors that mimic the epithelial component of human WT.

Spreafico F, Notarangelo LD, Schumacher RF, et al.
Clinical and molecular description of a Wilms tumor in a patient with tuberous sclerosis complex.
Am J Med Genet A. 2011; 155A(6):1419-24 [PubMed] Related Publications
We report on a girl affected with tuberous sclerosis, carrying a germline de novo TSC2 mutation, c.4934-4935delTT, leading to a p.F1645CfsX7, who developed a unilateral Wilms tumor (WT). Molecular investigation of the tumor biopsy at diagnosis revealed the loss of the constitutional wild-type TSC2 allele, and loss of heterozygosity for the WT1 gene. Deletion of the WTX gene was also present, but it involved the functionally inactive X chromosome. No mutation affecting the remaining WT1 and WTX alleles, as well as the CTNNB1 gene was found. Pathological examination of the surgical specimen documented the presence of diffuse anaplasia and p53 immunoreactivity. To the best of our knowledge, this is the second report of a patient with tuberous sclerosis who developed a WT, and it represents the first case in which a detailed clinical and molecular description is provided.

Md Zin R, Murch A, Charles A
Pathology, genetics and cytogenetics of Wilms' tumour.
Pathology. 2011; 43(4):302-12 [PubMed] Related Publications
Wilms' tumour (WT) is an embryonal cancer of childhood and is thought to be derived from embryonic kidney precursor cells. The Knudson two hit model was initially thought to occur in WT, but findings emerging from genetic and cytogenetic studies in the past two decades have implicated several genetic events. Recent techniques in genetic analysis have improved our ability to characterise changes in genes involved in WT which include WT1, CTNNB1, IGF2 and WTX. These genetic events have not only provided insight into the pathobiology of this malignancy, but the recognition of these candidate genes may offer potential targets for novel therapies. In this review, we will provide an overview of the pathological, genetic and cytogenetic characteristics of WT.

Pode-Shakked N, Harari-Steinberg O, Haberman-Ziv Y, et al.
Resistance or sensitivity of Wilms' tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target.
Oncogene. 2011; 30(14):1664-80 [PubMed] Related Publications
Wilms' tumor (WT), the most frequent renal solid tumor in children, has been linked to aberrant Wnt signaling. Herein, we demonstrate that different WTs can be grouped according to either sensitivity or resistance to an antibody (Ab) specific to frizzled7 (FZD7), a Wnt receptor. In the FZD7-sensitive WT phenotype, the Ab induced cell death of the FZD7(+) fraction, which in turn depleted primary WT cultures of their clonogenic and sphere-forming cells and decreased in vivo proliferation and survival on xenografting to the chick chorio-allantoic-membrane. In contrast, FZD7-resistant WT in which no cell death was induced showed a different intra-cellular route of the Ab-FZD7 complex compared with sensitive tumors and accumulation of β-catenin. This coincided with a low sFRP1 and DKK1 (Wnt inhibitors) expression pattern, restored epigenetically with de-methylating agents, and lack of β-catenin or WTX mutations. The addition of exogenous DKK1 and sFRP1 to the tumor cells enabled the sensitization of FZD7-resistant WT to the FZD7 Ab. Finally, although extremely difficult to achieve because of dynamic cellular localization of FZD7, sorting of FZD7(+) cells from resistant WT, showed them to be highly clonogenic/proliferative, overexpressing WT 'stemness' genes, emphasizing the importance of targeting this fraction. FZD7 Ab therapy alone or in combination with Wnt pathway antagonists may have a significant role in the treatment of WT via targeting of a tumor progenitor population.

[Establishment of BGC-823/WTX-EGFP gastric cancer cell line stably expressing Wilms tumor gene on X chromosome].
Nan Fang Yi Ke Da Xue Xue Bao. 2011; 31(3):392-6 [PubMed] Related Publications
OBJECTIVE: To establish the BGC-823/WTX-EGFP gastric cancer cell line with stable expression of Wilms tumor gene on the X chromosome (MTX) for functional analysis of WTX gene.
METHODS: The full-length WTX cDNA was amplified from human embryonic kidney 293FT cells and cloned into the pEGFP-N1 vector containing the reporter gene of green fluorescence protein. The recombinant pEGFP-WTX expression vector, after digestion by restriction enzyme to identify the size of target gene fragment, was transfected into 293FT cells and the expression of fluorescent reporter gene was observed under fluorescence microscope. pEGFP-WTX vector was transfected into human gastric cancer BGC-823 cell line to establish BGC-823/WTX-EGFP cell line stably expressing WTX. Quantitative RT-PCR and immunocytochemical staining were used to detect the expression of WTX in both BGC-823/WTX-EGFP and control BGC-823 cells.
RESULTS: The recombinant pEGFP-WTX plasmid was successfully constructed and verified by PCR and sequencing. The mRNA and protein expressions of MTX were significantly increased in BGC-823/WTX-EGFP cells as compared with those in the control cells.
CONCLUSION: The full-length WTX expression vector (pEGFP-WTX) and BGC-823/WTX-EGFP gastric cancer cell line have been successfully established to facilitate further functional study of WTX gene.

QingLing Z, LiNa Y, Li L, et al.
LMP1 antagonizes WNT/β-catenin signalling through inhibition of WTX and promotes nasopharyngeal dysplasia but not tumourigenesis in LMP1(B95-8) transgenic mice.
J Pathol. 2011; 223(5):574-83 [PubMed] Related Publications
Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) can induce cell transformation and tumourigenesis, but the mechanism is not understood. Previous studies have suggested that LMP1 acts through up-regulation of cellular proliferation pathways including the Wnt/β-catenin pathway, in which β-catenin is the central effector. Increased levels of β-catenin coupled with a decrease in E-cadherin lead to reduced cell adhesion. This pathway is antagonized by WTX (Wilms' tumour gene on the X chromosome), which can promote the ubiquitination and degradation of β-catenin. In the present study, we established L2/LMP1B(95 - 8) /EGFP transgenic mice to investigate the in vivo role of LMP1. Down-regulation of WTX and E-cadherin was accompanied by increased expression of β-catenin in these mice. Even though invasive tumours did not develop, dysplasia was seen in the nasopharynx and oropharynx epithelium of these transgenic mice. Analysis of LMP1(+) , WTX(+) , and LMP1 siRNA silenced HNE-1 cell lines demonstrated that WTX could exert a dominant role in LMP1-mediated WNT/β-catenin pathway regulation. This study indicates that LMP1 antagonizes the WNT/β-catenin pathway by inhibiting WTX, and this reduction in WTX is associated with epithelial dysplasia via regulation of the WNT/β-catenin pathway molecules E-cadherin and β-catenin. Further studies are required for a better understanding of the relationship between LMP1-mediated antagonization of the WNT/β-catenin pathway and tumourigenesis.

Perotti D, Radice P
Is WTX a suitable target for cancer therapy?
Pediatr Blood Cancer. 2011; 56(4):682 [PubMed] Related Publications

Huff V
Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene.
Nat Rev Cancer. 2011; 11(2):111-21 [PubMed] Free Access to Full Article Related Publications
Genes identified as being mutated in Wilms' tumour include TP53, a classic tumour suppressor gene (TSG); CTNNB1 (encoding β-catenin), a classic oncogene; WTX, which accumulating data indicate is a TSG; and WT1, which is inactivated in some Wilms' tumours, similar to a TSG. However, WT1 does not always conform to the TSG label, and some data indicate that WT1 enhances cell survival and proliferation, like an oncogene. Is WT1 a chameleon, functioning as either a TSG or an oncogene, depending on cellular context? Are these labels even appropriate for describing and understanding the function of WT1?

Perlman EJ, Grundy PE, Anderson JR, et al.
WT1 mutation and 11P15 loss of heterozygosity predict relapse in very low-risk wilms tumors treated with surgery alone: a children's oncology group study.
J Clin Oncol. 2011; 29(6):698-703 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Children's Oncology Group defines very low-risk Wilms tumors (VLRWT) as stage I favorable histology Wilms tumors weighing less than 550 g in children younger than 24 months of age. VLRWTs may be treated with nephrectomy alone. However, 10% to 15% of VLRWTs relapse without chemotherapy. Previous studies suggest that VLRWTs with low WT1 expression and/or 11p15 loss of heterozygosity (LOH) may have increased risk of relapse. The current study validates these findings within prospectively identified children with VLRWT who did not receive adjuvant chemotherapy.
PATIENTS AND METHODS: Fifty-six VLRWTs (10 relapses) were analyzed for mutation of WT1, CTNNB1, and WTX; for 11p15 LOH using microsatellite analysis; and for H19DMR and KvDMR1 methylation.
RESULTS: 11p15 LOH was identified in 19 (41%) of 46 evaluable VLRWTs and was significantly associated with relapse (P < .001); 16 of 19 were isodisomic for 11p15. WT1 mutation was identified in nine (20%) of 45 evaluable VLRWTs and was significantly associated with relapse (P = .004); all nine cases also had 11p15 LOH. All evaluable tumors showing LOH by microsatellite analysis also showed LOH by methylation analysis. Retention of the normal imprinting pattern was identified in 24 of 42 evaluable tumors, and none relapsed. Loss of imprinting at 11p15 was identified in one of 42 tumors.
CONCLUSION: WT1 mutation and 11p15 LOH are associated with relapse in patients with VLRWTs who do not receive chemotherapy. These may provide meaningful biomarkers to stratify patients for reduced chemotherapy in the future. VLRWTs show a different incidence of WT1 mutation and 11p15 imprinting patterns than has been reported in Wilms tumors of all ages.

Gaujoux S, Pinson S, Gimenez-Roqueplo AP, et al.
Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers.
Clin Cancer Res. 2010; 16(21):5133-41 [PubMed] Related Publications
PURPOSE: In adrenocortical tumors (ACT), Wnt/β-catenin pathway activation can be explained by β-catenin somatic mutations only in a subset of tumors. ACT is observed in patients with familial adenomatous polyposis (FAP) with germline APC mutations, as well as in patients with Beckwith-Wiedemann syndrome with Wilms' tumors reported to have WTX somatic mutations. Both APC and WTX are involved in Wnt/β-catenin pathway regulation and may play a role in ACT tumorigenesis. The aim of this study was to report if APC and WTX may be associated with FAP-associated and sporadic ACT.
EXPERIMENTAL DESIGN: ACTs from patients with FAP and sporadic adrenocortical carcinomas (ACC) with abnormal β-catenin localization on immunohistochemistry but no somatic β-catenin mutations were studied. APC was analyzed by denaturing high-performance liquid chromatography followed by direct sequencing and by multiplex ligation-dependent probe amplification when allelic loss was suspected. WTX was studied by direct sequencing.
RESULTS: Four ACTs were observed in three patients with FAP and were ACC, adrenocortical adenoma, and bilateral macronodular adrenocortical hyperplasia, all with abnormal β-catenin localization. Biallelic inactivation of APC was strongly suggested by the simultaneous existence of somatic and germline alterations in all ACTs. In the 20 sporadic ACCs, a silent heterozygous somatic mutation as well as a rare heterozygous polymorphism in APC was found. No WTX mutations were observed.
CONCLUSIONS: ACT should be considered a FAP tumor. Biallelic APC inactivation mediates activation of the Wnt/β-catenin pathway in the ACTs of patients with FAP. In contrast, APC and WTX genetic alterations do not play a significant role in sporadic ACC.

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