Gene Summary

Gene:WT2; Wilms tumor 2
Aliases: ADCR, MTACR1
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Wilms' tumors frequently have a maternal-specific loss of heterozygosity (LOH) on human chromosome 11p15.5 There has been a longstanding search to identify a gene, refered to as WT2, in this region that plays a role in Wilms' tumorigenesis.

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: WT2 (cancer-related)

Liu Z, He F, OuYang S, et al.
miR-140-5p could suppress tumor proliferation and progression by targeting TGFBRI/SMAD2/3 and IGF-1R/AKT signaling pathways in Wilms' tumor.
BMC Cancer. 2019; 19(1):405 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action.
METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified.
RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p.
CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.

Zidanloo SG, Colagar AH, Ayatollahi H, Bagheryan Z
G-quadruplex forming region within WT1 promoter is selectively targeted by daunorubicin and mitoxantrone: A possible mechanism for anti-leukemic effect of drugs.
J Biosci. 2019; 44(1) [PubMed] Related Publications
Wilms tumor 1

Ni D, Liu J, Hu Y, et al.
A1CF-Axin2 signal axis regulates apoptosis and migration in Wilms tumor-derived cells through Wnt/β-catenin pathway.
In Vitro Cell Dev Biol Anim. 2019; 55(4):252-259 [PubMed] Related Publications
A1CF, a complementary factor of APOBEC-1, is involved in many cellular processes for its mRNA editing role, such as cell proliferation, apoptosis, and migration. Here, we explored the regulatory function of A1CF in Wilms tumor-derived cells. Quantitative real-time PCR was performed to detect the mRNA level of A1CF, Axin2, β-Catenin, CCND1 or NKD1 in A1CF-depleted or A1CF-overexpression G401 cells. Western bolt was used to analyze the expression of A1CF, Axin2, and β-catenin protein. The cell apoptosis and migration ability were determined using flow cytometry assay or wound healing, respectively. Our study demonstrated that overexpression of A1CF, Axin2 was upregulated and knockdown of A1CF decreased Axin2 expression at mRNA and protein levels in G401 cells. Besides, knockdown of A1CF further upregulated β-catenin, the classical regulator of Wnt signal pathway, and increased CCND1 and NKD1, the target genes of Wnt/β-catenin. Furthermore, overexpression of Axin2 partly rescued the expression of β-catenin in A1CF-deficiency stable G401 cells. In Wnt agonist BML-284 treated G401 cells, A1CF was increased like other classical regulator of Wnt signal pathway, such as Axin2 and β-catenin. Meanwhile, knockdown of Axin2 rescued β-catenin expression which was decreased in A1CF overexpression condition with BML-284. Further, overexpression of A1CF reduced cell apoptosis but promoted cell migration, and overexpression of Axin2 got similar results. In A1CF-decreased stable G401 cells, overexpression of Axin2 partly rescued the cell apoptosis and migration. We find that A1CF is a positive regulator of Axin2, a Wnt/β-catenin pathway inhibitor, and A1CF-Axin2 signal axis regulates Wilms tumor-derived cells' apoptosis and migration through Axin2.

Wang X, Song P, Huang C, et al.
Weighted gene co‑expression network analysis for identifying hub genes in association with prognosis in Wilms tumor.
Mol Med Rep. 2019; 19(3):2041-2050 [PubMed] Free Access to Full Article Related Publications
Wilms tumor (WT) is the most common type of renal malignancy in children. Survival rates are low and high‑risk WT generally still carries a poor prognosis. To better elucidate the pathogenesis and tumorigenic pathways of high‑risk WT, the present study presents an integrated analysis of RNA expression profiles of high‑risk WT to identify predictive molecular biomarkers, for the improvement of therapeutic decision‑making. mRNA sequence data from high‑risk WT and adjacent normal samples were downloaded from The Cancer Genome Atlas to screen for differentially expressed genes (DEGs) using R software. From 132 Wilms tumor samples and six normal samples, 2,089 downregulated and 941 upregulated DEGs were identified. In order to identify hub DEGs that regulate target genes, weighted gene co‑expression network analysis (WGCNA) was used to identify 11 free‑scale gene co‑expressed clusters. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were annotated using KEGG Orthology Based Annotation System annotation of different module genes. The Search Tool for the Retrieval of Interacting Genes was used to construct a protein‑protein interaction network for the identified DEGs, and the hub genes of WGCNA modules were identified using the Cytohubb plugin with Cytoscape software. Survival analysis was subsequently performed to highlight hub genes with a clinical signature. The present results suggest that epidermal growth factor, cyclin dependent kinase 1, endothelin receptor type A, nerve growth factor receptor, opa‑interacting protein 5, NDC80 kinetochore complex component and cell division cycle associated 8 are essential to high‑risk WT pathogenesis, and they are closely associated with clinical prognosis.

Armstrong AE, Gadd S, Huff V, et al.
A unique subset of low-risk Wilms tumors is characterized by loss of function of TRIM28 (KAP1), a gene critical in early renal development: A Children's Oncology Group study.
PLoS One. 2018; 13(12):e0208936 [PubMed] Free Access to Full Article Related Publications
This study explores the genomic alterations that contribute to the formation of a unique subset of low-risk, epithelial differentiated, favorable histology Wilms tumors (WT), tumors that have been characterized by their expression of post-induction renal developmental genes (Subset 1 WT). We demonstrate copy neutral loss of heterozygosity involving 19q13.32-q13.43, unaccompanied by evidence for imprinting by DNA methylation. We further identified loss-of-function somatic mutations in TRIM28 (also known as KAP1), located at 19q13, in 8/9 Subset 1 tumors analyzed. An additional germline TRIM28 mutation was identified in one patient. Retrospective evaluation of previously analyzed WT outside of Subset 1 identified an additional tumor with anaplasia and both TRIM28 and TP53 mutations. A major function of TRIM28 is the repression of endogenous retroviruses early in development. We depleted TRIM28 in HEK293 cells, which resulted in increased expression of endogenous retroviruses, a finding also demonstrated in TRIM28-mutant WT. TRIM28 has been shown by others to be active during early renal development, and to interact with WTX, another gene recurrently mutated in WT. Our findings suggest that inactivation of TRIM28 early in renal development contributes to the formation of this unique subset of FHWTs, although the precise manner in which TRIM28 impacts both normal renal development and oncogenesis remains elusive.

Su H, Wang X, Song J, et al.
MicroRNA-539 inhibits the progression of Wilms' Tumor through downregulation of JAG1 and Notch1/3.
Cancer Biomark. 2019; 24(1):125-133 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previous studies demonstrated that miR-539 play an important role in the carcinogenesis of some cancers. The aim of the present study was to determine the role of miR-539 in the pathogenesis of Wilms' Tumor (WT).
METHODS: The expression level of miR-539 was measured by qRT-PCR in 42 WT tissues and SK-NEP-1 cell line. Protein expression of genes (E-cadherin, N-cadherin, Vimentin, Notch 1, Notch 3 and JAG1) was assessed by Western blot. The function of miR-539 was investigated in SK-NEP-1 cells by MTT and Transwell assays. The relationship between miR-539 and JAG1 was verified by a dual luciferase assay in SK-NEP-1 cells.
RESULTS: The expression level of miR-539 was significantly decreased in WT tissues. Downregulation of miR-539 was closely related to NWTS-5 stage, lymph node metastasis and histological type of WT patients. Furthermore, low miR-539 expression was associated with a shorter overall survival rate in WT patients. In vitro, overexpression of miR-539 suppressed proliferation, migration and invasion of SK-NEP-1 cells. In addition, JAG1 was a direct target of miR-539. MiR-539 inhibited the development of WT by inhibiting JAG1-Notch1/3 expressing and blocking EMT.
CONCLUSION: MiR-539 inhibited the progression of WT through downregulation of JAG1 and Notch1/3.

Haruta M, Arai Y, Okita H, et al.
Combined Genetic and Chromosomal Characterization of Wilms Tumors Identifies Chromosome 12 Gain as a Potential New Marker Predicting a Favorable Outcome.
Neoplasia. 2019; 21(1):117-131 [PubMed] Free Access to Full Article Related Publications
To identify prognostic factors, array CGH (aCGH) patterns and mutations in WT1 and 9 other genes were analyzed in 128 unilateral Wilms tumors (WTs). Twenty patients had no aCGH aberrations, and 31 had WT1 alterations [silent and WT1 types: relapse-free survival (RFS), 95% and 83%, respectively]. Seventy-seven patients had aCGH changes without WT1 alterations (nonsilent/non-WT1 type) and were subtyped into those with or without +12, 11q-, 16q-, or HACE1 loss. RFS was better for those with than those without +12 (P = .010) and worse for those with than those without 11q-, 16q-, or HACE1 loss (P = .001, .025, or 1.2E-04, respectively). Silent and WT1 type and 8 subtype tumors were integrated and classified into 3 risk groups: low risk for the silent type and +12 subgroup; high risk for the no +12 plus 11q-, 16q-, or HACE1 loss subgroup; intermediate risk for the WT1 type and no +12 plus no 11q-, 16q-, or HACE1 loss subgroup. Among the 27 WTs examined, the expression of 146 genes on chromosome 12 was stronger in +12 tumors than in no +12 tumors, while that of 10 genes on 16q was weaker in 16q- tumors than in no 16q- tumors. Overexpression in 75 out of 146 upregulated genes and underexpression in 7 out of 10 downregulated genes correlated with better and worse overall survival, respectively, based on the public database. +12 was identified as a potential new marker predicting a favorable outcome, and chromosome abnormalities may be related to altered gene expression associated with these abnormalities.

Kruber P, Angay O, Winkler A, et al.
Loss or oncogenic mutation of DROSHA impairs kidney development and function, but is not sufficient for Wilms tumor formation.
Int J Cancer. 2019; 144(6):1391-1400 [PubMed] Related Publications
Wilms tumor (WT) is the most common kidney cancer in childhood. Mutations in the microprocessor genes DROSHA and DGCR8 have been identified as putative oncogenic drivers, indicating a critical role of aberrant miRNA processing in WT formation. To characterize the in vivo role of DROSHA mutations during kidney development and their oncogenic potential, we analyzed mouse lines with either a targeted deletion of Drosha or an inducible expression of human DROSHA carrying a tumor-specific E1147K mutation that acts in a dominant negative manner. Both types of mutation induce striking changes in miRNA patterns. Six2-cre mediated deletion of Drosha in nephron progenitors led to perinatal lethality with apoptotic loss of progenitor cells and early termination of nephrogenesis. Mosaic deletions via Wt1-cre

Gu X, Coates PJ, Boldrup L, et al.
Copy number variation: A prognostic marker for young patients with squamous cell carcinoma of the oral tongue.
J Oral Pathol Med. 2019; 48(1):24-30 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The incidence of squamous cell carcinoma of the oral tongue (SCCOT) is increasing in people under age 40. There is an urgent need to identify prognostic markers that help identify young SCCOT patients with poor prognosis in order to select these for individualized treatment.
MATERIALS AND METHODS: To identify genetic markers that can serve as prognostic markers for young SCCOT patients, we first investigated four young (≤40 years) and five elderly patients (≥50 years) using global RNA sequencing and whole-exome sequencing. Next, we combined our data with data on SCCOT from the cancer genome atlas (TCGA), giving a total of 16 young and 104 elderly, to explore the correlations between genomic variations and clinical outcomes.
RESULTS: In agreement with previous studies, we found that SCCOT from young and elderly patients was transcriptomically and also genomically similar with no significant differences regarding cancer driver genes, germline predisposition genes, or the burden of somatic single nucleotide variations (SNVs). However, a disparate copy number variation (CNV) was found in young patients with distinct clinical outcome. Combined with data from TCGA, we found that the overall survival was significantly better in young patients with low-CNV (n = 5) compared to high-CNV (n = 11) burden (P = 0.044).
CONCLUSIONS: Copy number variation burden is a useful single prognostic marker for SCCOT from young, but not elderly, patients. CNV burden thus holds promise to form an important contribution when selecting suitable treatment protocols for young patients with SCCOT.

Phelps HM, Al-Jadiry MF, Corbitt NM, et al.
Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.
World J Pediatr. 2018; 14(6):585-593 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.
METHODS: Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.
RESULTS: Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).
CONCLUSIONS: These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.

Ueno-Yokohata H, Okita H, Nakasato K, et al.
Preoperative diagnosis of clear cell sarcoma of the kidney by detection of BCOR internal tandem duplication in circulating tumor DNA.
Genes Chromosomes Cancer. 2018; 57(10):525-529 [PubMed] Related Publications
Clear cell sarcoma of the kidney (CCSK) is the second most common renal malignancy in children. The prognosis is poorer in CCSK than in Wilms' tumor, and multimodal treatment including surgery, intensive chemotherapy, and radiation is required to improve the outcome for children with CCSK. Histological evaluation is required for the diagnosis. However, biopsies of tumors to obtain diagnostic specimens are not routinely performed because of the risk of spreading tumor cells during the procedure. Recently, internal tandem duplication (ITD) of BCOR has been recognized as a genetic hallmark of CCSK. We herein established a novel BCOR-ITD-specific polymerase chain reaction method with well-designed primers, and then performed a liquid biopsy for cell-free DNA (cfDNA) obtained from plasma of three children with nonmetastatic renal tumors (stage II) and from one control. BCOR-ITD was positively detected in the cfDNA of two cases, both of which were later diagnosed as CCSK based on histological feature of the resected tumor specimen, while it was not detected for a normal control and a patient diagnosed with Wilms' tumor. Our study is the first one of preoperative circulating tumor DNA assay in pediatric renal tumors. The liquid biopsy method enables less invasive, preoperative diagnosis of CCSK with no risk of tumor spillage, which can avoid iatrogenic upstaging.

Bharathavikru R, Hastie ND
Overgrowth syndromes and pediatric cancers: how many roads lead to
Genes Dev. 2018; 32(15-16):993-995 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Overgrowth syndromes such as Perlman syndrome and associated pediatric cancers, including Wilms tumor, arise through genetic and, in certain instances, also epigenetic changes. In the case of the Beckwith-Wiedemann overgrowth syndrome and in Wilms tumor, increased levels of

Trink A, Kanter I, Pode-Shakked N, et al.
Geometry of Gene Expression Space of Wilms' Tumors From Human Patients.
Neoplasia. 2018; 20(8):871-881 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Wilms' tumor is a pediatric malignancy that is thought to originate from faulty kidney development during the embryonic stage. However, there is a large variation between tumors from different patients in both histology and gene expression that is not well characterized. Here we use a meta-analysis of published microarray datasets to show that Favorable Histology Wilms' Tumors (FHWT's) fill a triangle-shaped continuum in gene expression space of which the vertices represent three idealized "archetypes". We show that these archetypes have predominantly renal blastemal, stromal, and epithelial characteristics and that they correlate well with the three major lineages of the developing embryonic kidney. Moreover, we show that advanced stage tumors shift towards the renal blastemal archetype. These results illustrate the potential of this methodology for characterizing the cellular composition of Wilms' tumors and for assessing disease progression.

Chen KS, Stroup EK, Budhipramono A, et al.
Mutations in microRNA processing genes in Wilms tumors derepress the
Genes Dev. 2018; 32(15-16):996-1007 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor

Valind A, Wessman S, Pal N, et al.
Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers.
Pediatr Blood Cancer. 2018; 65(11):e27301 [PubMed] Related Publications
Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, with somatic inactivation of the second allele occurring through 11p loss of heterozygosity. The time point of this second hit has remained unknown. We analyzed seven Wilms tumors from two patients with constitutional WT1 mutations by whole exome sequencing and genomic array. All tumors exhibited wild type WT1 loss through uniparental isodisomy. Each tumor had a unique genomic breakpoint in 11p, typically accompanied by a private activating mutation of CTNNB1. Hence, convergent evolution rather than field carcinogenesis underlies multifocal tumors in WT1 mutation carriers.

Tan HY, Wang N, Li S, et al.
Repression of WT1-Mediated LEF1 Transcription by Mangiferin Governs β-Catenin-Independent Wnt Signalling Inactivation in Hepatocellular Carcinoma.
Cell Physiol Biochem. 2018; 47(5):1819-1834 [PubMed] Related Publications
BACKGROUND/AIMS: The development of hepatocellular carcinoma (HCC) is a complex process which involves deregulation of multiple signalling pathways. The hyper-activation of Wnt signalling promotes sustained expansion, invasion, and neovascularization of HCC. Mangiferin, a natural small molecule present in Mangifera indica L. has been shown to inactivate β-catenin, which is an indispensable regulator in Wnt pathway. Our study aimed to determine whether mangiferin has any inhibitory effect on HCC and examine how it modulates Wnt signalling.
METHODS: The tumour inhibitory effect of mangiferin was examined by in vitro cellular models and an in vivo orthotopic HCC implantation model. The genes responsible for mangiferin-mediated anti-HCC were delineated by polymerase chain reaction (PCR) microarray. The expression of target genes was further determined by quantitative PCR and immuno-blotting assays. The binding capacity of Wilms' tumour 1 (WT1) to the lymphoid enhancer-binding factor 1 (LEF1) promoter was confirmed by chromatin immunoprecipitation-qPCR.
RESULTS: Oral administration of mangiferin inhibited orthotopic tumour growth. Cellular investigations confirmed the dose-dependent inhibition of mangiferin on HCC expansion and invasion. PCR array combined with Gene Ontology analysis revealed that the Wnt pathway was the predominant target of mangiferin and LEF1 was the most reduced gene in the Wnt pathway. Overexpression of LEF1 diminished repression of Wnt signalling and reduced proliferation activity in mangiferin-treated HCC cells. The mangiferin-mediated down-regulation of LEF1 was independent of β-catenin but associated with WT1 protein. WT1 knock-in in HCC cells further enhanced LEF1 expression. Chromatin immunoprecipitation assays revealed that the mangiferin induced repression of LEF1 was associated with decreased occupancy of WT1 on the LEF1 promoter.
CONCLUSION: Our study identifies a novel mechanism of hepatocellular carcinoma inhibition through β-catenin-independent Wnt signalling, which is regulated by WT1-associated LEF1 repression. The study also highlights mangiferin as a promising Wnt inhibitor for HCC treatment.

Hunter RW, Liu Y, Manjunath H, et al.
Loss of
Genes Dev. 2018; 32(13-14):903-908 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels. Rather, analysis of

Zhu J, Jia W, Wu C, et al.
Base Excision Repair Gene Polymorphisms and Wilms Tumor Susceptibility.
EBioMedicine. 2018; 33:88-93 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Base excision repair (BER) is the main mechanism to repair endogenous DNA lesions caused by reactive oxygen species. BER deficiency is linked with cancer susceptibility and premature aging. Single nucleotide polymorphisms (SNPs) within BER genes have been implicated in various human malignancies. Nevertheless, a comprehensive investigation of their association with Wilms tumor susceptibility is lacking. In this study, 145 cases and 531 sex and age-matched healthy controls were recruited. We systematically genotyped 18 potentially functional SNPs in six core BER pathway genes, using a candidate SNP approach. Logistic regression was employed to evaluate odds ratio (OR) and 95% confidence interval (CI) adjusted for age and gender. Several SNPs showed protective effects against Wilms tumor. Significant associations with Wilms tumor susceptibility were shown for hOGG1 rs1052133 (dominant: adjusted OR = 0.66, 95% CI = 0.45-0.96, P = .030), FEN1 rs174538 (dominant: adjusted OR = 0.66, 95% CI = 0.45-0.95, P = .027; recessive: adjusted OR = 0.54, 95% CI = 0.32-0.93 P = .027), and FEN1 rs4246215 (dominant: adjusted OR = 0.55, 95% CI = 0.38-0.80, P = .002) polymorphisms. Stratified analysis was performed by age, gender, and clinical stage. Moreover, there was evidence of functional implication of these significant SNPs suggested by online expression quantitative trait locus (eQTL) analysis. Our findings indicate that common SNPs in BER genes modify susceptibility to Wilms tumor.

Fang D, Gan H, Cheng L, et al.
H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers.
Elife. 2018; 7 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.

Wegert J, Vokuhl C, Collord G, et al.
Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants.
Nat Commun. 2018; 9(1):2378 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.

Dabrowski E, Armstrong AE, Leeth E, et al.
Proximal Hypospadias and a Novel
Pediatrics. 2018; 141(Suppl 5):S491-S495 [PubMed] Related Publications
We present a case of an infant with proximal hypospadias, penoscrotal transposition, and bilaterally descended testes found to have a clinically significant

Royer-Pokora B, Beier M, Brandt A, et al.
Chemotherapy and terminal skeletal muscle differentiation in WT1-mutant Wilms tumors.
Cancer Med. 2018; 7(4):1359-1368 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Wilms tumors (WT) with WT1 mutations do not respond well to preoperative chemotherapy by volume reduction, suggesting resistance to chemotherapy. The histologic pattern of this tumor subtype indicates an intrinsic mesenchymal differentiation potential. Currently, it is unknown whether cytotoxic treatments can induce a terminal differentiation state as a direct comparison of untreated and chemotherapy-treated tumor samples has not been reported so far. We conducted gene expression profiling of 11 chemotherapy and seven untreated WT1-mutant Wilms tumors and analyzed up- and down-regulated genes with bioinformatic methods. Cell culture experiments were performed from primary Wilms tumors and genetic alterations in WT1 and CTNNB1 analyzed. Chemotherapy induced MYF6 165-fold and several MYL and MYH genes more than 20-fold and repressed many genes from cell cycle process networks. Viable tumor cells could be cultivated when patients received less than 8 weeks of chemotherapy but not in two cases with longer treatments. In one case, viable cells could be extracted from a lung metastasis occurring after 6 months of intensive chemotherapy and radiation. Comparison of primary tumor and metastasis cells from the same patient revealed up-regulation of RELN and TBX2, TBX4 and TBX5 genes and down-regulation of several HOXD genes. Our analyses demonstrate that >8 weeks of chemotherapy can induce terminal myogenic differentiation in WT1-mutant tumors, but this is not associated with volume reduction. The time needed for all tumor cells to achieve the terminal differentiation state needs to be evaluated. In contrast, prolonged treatments can result in genetic alterations leading to resistance.

Wang D, Horton JR, Zheng Y, et al.
Role for first zinc finger of WT1 in DNA sequence specificity: Denys-Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites.
Nucleic Acids Res. 2018; 46(8):3864-3877 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Wilms tumor protein (WT1) is a Cys2-His2 zinc-finger transcription factor vital for embryonic development of the genitourinary system. The protein contains a C-terminal DNA binding domain with four tandem zinc-fingers (ZF1-4). An alternative splicing of Wt1 can add three additional amino acids-lysine (K), threonine (T) and serine (S)-between ZF3 and ZF4. In the -KTS isoform, ZF2-4 determine the sequence-specificity of DNA binding, whereas the function of ZF1 remains elusive. Three X-ray structures are described here for wild-type -KTS isoform ZF1-4 in complex with its cognate DNA sequence. We observed four unique ZF1 conformations. First, like ZF2-4, ZF1 can be positioned continuously in the DNA major groove forming a 'near-cognate' complex. Second, while ZF2-4 make base-specific interactions with one DNA molecule, ZF1 can interact with a second DNA molecule (or, presumably, two regions of the same DNA molecule). Third, ZF1 can intercalate at the joint of two tail-to-head DNA molecules. If such intercalation occurs on a continuous DNA molecule, it would kink the DNA at the ZF1 binding site. Fourth, two ZF1 units can dimerize. Furthermore, we examined a Denys-Drash syndrome-associated ZF1 mutation (methionine at position 342 is replaced by arginine). This mutation enhances WT1 affinity for a guanine base. X-ray crystallography of the mutant in complex with its preferred sequence revealed the interactions responsible for this affinity change. These results provide insight into the mechanisms of action of WT1, and clarify the fact that ZF1 plays a role in determining sequence specificity of this critical transcription factor.

Martins AG, Pinto AT, Domingues R, Cavaco BM
Identification of a novel CTR9 germline mutation in a family with Wilms tumor.
Eur J Med Genet. 2018; 61(5):294-299 [PubMed] Related Publications
Germline mutations in the WT1 gene have been identified in some families with Wilms tumor. Recently, the CTR9 gene was found to be mutated in three families with Wilms tumor, thus representing a novel predisposition gene for this disease. We identified a family with a history of Wilms tumor characterized by three affected siblings, one of them presenting an aggressive bilateral tumor. Here we investigated the involvement of WT1 and CTR9 genes in this family with Wilms tumor. The involvement of WT1 was first evaluated by Next generation sequencing in leukocytes DNA from one affected family member. Subsequently, the CTR9 gene was analyzed by Sanger sequencing in DNA and RNA from patients' leukocytes and/or tumor. No mutations were detected in WT1. However, we identified a novel CTR9 germline variant, located in a consensus splice acceptor site, which was found to segregate with Wilms tumor in this family. We found that this variant leads to the skipping of the entire exon 9 in the mRNA, which is predicted to encode a truncated CTR9 protein, strongly suggesting that it is pathogenic. Additionally, we also detected loss of heterozygosity in the index case tumor, which is consistent with CTR9 being a tumor suppressor gene, confirming also its contribution to familial Wilms tumor etiology. The identification of a novel CTR9 germline mutation will improve the present knowledge on the molecular basis of familial Wilms tumor. Importantly, it will help in the genetic counselling and may also lead to earlier diagnosis in other family members and future generations.

Zhu S, Fu W, Zhang L, et al.
LINC00473 antagonizes the tumour suppressor miR-195 to mediate the pathogenesis of Wilms tumour via IKKα.
Cell Prolif. 2018; 51(1) [PubMed] Related Publications
OBJECTIVES: Although dramatic improvements of overall survival has achieved in patients with favourable histology Wilms tumour, disease recurrence is still the main cause of cancer-related death in childhood. Long non-coding RNAs (lncRNAs) as oncogenes or tumour suppressors are dysregulated during carcinogenesis. However, the role of lncRNAs in the pathogenesis of Wilms tumour is unknown. Here, an lncRNA LINC00473 signature that functioned as oncogene was identified in Wilms tumour.
METHODS: Wilms tumour (n = 15) and relative normal tissues were collected. The LINC00473 expression and function in Wilms tumour was determined. The LncRNA-miRNA network of LINC00473 was analysed in vitro and vivo.
RESULTS: We uncovered that the expression of LINC00473 was elevated in tumour tissues than that in relative normal tissues. Higher LINC00473 levels correlated to higher stage and unfavourable histology Wilms tumour. Mechanistically, knockdown of LINC00473 inhibited cell vitality and induced Bcl-2-dependent apoptosis and G1/S arrest via CDK2 and cyclin D1. Moreover, LINC00473 harboured binding sites for miR-195 and limited miR-195 availability in a dose-dependent manner. Forced expression of miR-195 impaired tumour survival and metastasis, which, however, could be restored by LINC00473. Furthermore, IKKα was the downstream of LINC00473/miR-195 signals and could be directly targeted by miR-195 to participate LINC00473-induced tumour progression. Loss-of-function of LINC00473 in vivo effectively promoted the regression of Wilms tumour via miR-195/IKKα-mediated growth inhibition.
CONCLUSION: LINC00473 as an oncogene is up-regulated to participate into the molecular pathogenesis of Wilms tumour via miR-195/IKKα.

Takada Y, Sakai Y, Matsushita Y, et al.
Sustained endocrine profiles of a girl with WAGR syndrome.
BMC Med Genet. 2017; 18(1):117 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined.
CASE PRESENTATION: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions.
CONCLUSIONS: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.

Bissanum R, Lirdprapamongkol K, Svasti J, et al.
The role of WT1 isoforms in vasculogenic mimicry and metastatic potential of human triple negative breast cancer cells.
Biochem Biophys Res Commun. 2017; 494(1-2):256-262 [PubMed] Related Publications
Triple negative breast cancer (TNBC) is highly aggressive and has a few therapeutic treatments, so new targeted therapy and biomarkers are required to provide alternative choices for treating TNBC patients. Recent studies showed that vasculogenic mimicry (VM), the formation of blood channels by aggressive cancer cells that mimic endothelial cells, is a factor contributing to poor prognosis in TNBC. Wilms' tumor 1 (WT1) gene has been found to be highly expressed in TNBC, and has 4 major distinct isoforms; isoform A (-17AA/-KTS; -/-), isoform B (+17AA/-KTS; +/-), isoform C (-17AA/+KTS; -/+) and isoform D (+17AA/+KTS; +/+). The involvement of each WT1 isoform in TNBC progression remains largely unclear. In this study, WT1 isoform-overexpressing cell sublines were established from a TNBC cell line, MDA-MB-231, by stable transfection, and the aggressive behavior of the cell sublines were evaluated. Only the WT1 isoform B- and isoform C-overexpressing cell sublines showed the significant increase in VM forming capability compared to the parental cell line and other isoform cell sublines. qRT-PCR was used to explore the change in expression level of two VM-related genes, EphA2 and VE-cadherin. All WT1 isoform cell sublines showed up-regulation of EphA2 but the levels detected in the isoform B- and isoform C-cell sublines were higher than those observed in other cell sublines. In contrast, significant up-regulation of VE-cadherin was found only in isoform A- and isoform D-cell sublines. Isoform B- and isoform C-cell sublines showed higher rates of cell migration compared to those of other cell sublines, as determined by both wound healing and Transwell assays. Gelatin zymography revealed increased MMP-9 enzyme production in isoform D-cell subline compared to the parental cell line, but this change was not observed in other cell sublines. Western blot analysis showed significantly increased expression of β-catenin in isoform B- and isoform C-cell sublines, compared to parental cell line and other isoform cell sublines. In conclusion, our findings demonstrate that WT1 isoforms play different roles in modulating the VM-forming capacity and metastatic potential of TNBC cells.

Xie F, Hosany S, Zhong S, et al.
MicroRNA-193a inhibits breast cancer proliferation and metastasis by downregulating WT1.
PLoS One. 2017; 12(10):e0185565 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
In many cancers, microRNA-193a (miR-193a) is a suppressor miRNA, but its underlying anti-oncogenic activity in breast cancer is not known. In this study, we found decreased miR-193a (specifically, miR-193a-5p) expression not only in breast cancer cell lines but also in breast cancer tissues as compared with the adjacent non-tumor tissues. Ectopic miR-193a overexpression inhibited the proliferation, colony formation, migration, and invasion of MDA-MB-231 and BT549 cells. miR-193a reduced Wilms' tumor 1 (WT1) expression and repressed luciferase reporter activity by binding WT1 coding region sequences; mutation of the predicted miR-193a binding site abolished this effect. miR-193a and WT1 expression were significantly inversely correlated in breast cancer tissues. Importantly, the anti-cancer activity induced by miR-193a was partially reversed by WT1 overexpression, indicating an important role for WT1 in such activity related to miR-193a. Our results reveal that miR-193a-WT1 interaction plays an important role in breast cancer metastasis, and suggest that restoring miR-193a expression is a therapeutic strategy in breast cancer.

Pereira HS, Soares Lima SC, de Faria PS, et al.
Front Biosci (Elite Ed). 2018; 10:143-154 [PubMed] Related Publications
Wilms' tumor (WT) is the most frequent renal cancer in childhood, the occurrence of which is characterized by a relatively low frequency of associated mutations. While epigenetic alterations have been postulated to play a relevant role in the emergence of this tumor, the mechanisms involved in WT development remain largely unknown. In this study, the DNA methylation profile of WT was characterized with Beadchip array. Comparisons between WT with normal kidney identified 827 differentially methylated regions, most of which were attributable in hypermethylation in CpG islands. Among affected genes,

Tawara I, Kageyama S, Miyahara Y, et al.
Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS.
Blood. 2017; 130(18):1985-1994 [PubMed] Related Publications
Wilms' tumor 1 (WT1) is constantly expressed in leukemic cells of acute leukemia and myelodysplastic syndrome (MDS). A T-cell receptor (TCR) that specifically reacts with WT1 peptide in the context of HLA-A*24:02 has been identified. We conducted a first-in-human trial of TCR-gene transduced T-cell (TCR-T-cell) transfer in patients with refractory acute myeloblastic leukemia (AML) and high-risk MDS to investigate the safety and cell kinetics of the T cells. The WT1-specific TCR-gene was transduced to T cells using a retroviral vector encoding small interfering RNAs for endogenous TCR genes. The T cells were transferred twice with a 4-week interval in a dose-escalating design. After the second transfer, sequential WT1 peptide vaccines were given. Eight patients, divided into 2 dose cohorts, received cell transfer. No adverse events of normal tissue were seen. The TCR-T cells were detected in peripheral blood for 8 weeks at levels proportional to the dose administered, and in 5 patients, they persisted throughout the study period. The persisting cells maintained ex vivo peptide-specific immune reactivity. Two patients showed transient decreases in blast counts in bone marrow, which was associated with recovery of hematopoiesis. Four of 5 patients who had persistent T cells at the end of the study survived more than 12 months. These results suggest WT1-specific TCR-T cells manipulated by ex vivo culture of polyclonal peripheral lymphocytes survived in vivo and retained the capacity to mount an immune reaction to WT1. This trial was registered at www.umin.ac.jp as #UMIN000011519.

Further References

Dowdy SF, Fasching CL, Araujo D, et al.
Suppression of tumorigenicity in Wilms tumor by the p15.5-p14 region of chromosome 11.
Science. 1991; 254(5029):293-5 [PubMed] Related Publications
Wilms tumor has been associated with genomic alterations at both the 11p13 and 11p15 regions. To differentiate between the involvement of these two loci, a chromosome 11 was constructed that had one or the other region deleted, and this chromosome was introduced into the tumorigenic Wilms tumor cell line G401. When assayed for tumor-forming activity in nude mice, the 11p13-deleted, but not the 11p15.5-p14.1-deleted chromosome, retained its ability to suppress tumor formation. These results provide in vivo functional evidence for the existence of a second genetic locus (WT2) involved in suppressing the tumorigenic phenotype of Wilms tumor.

Wadey RB, Pal N, Buckle B, et al.
Loss of heterozygosity in Wilms' tumour involves two distinct regions of chromosome 11.
Oncogene. 1990; 5(6):901-7 [PubMed] Related Publications
Pairs of tumour and normal DNA samples from 38 Wilms' tumour patients have been investigated for loss of heterozygosity using 12 probes from chromosome 11. Allele loss was detected in only 11 cases (31%). Densitometric analysis showed that allele loss was not due to non-disjunction or hemizygous deletion, but rather to mitotic recombination or non-disjunction plus reduplication. Although the development of homozygosity sometimes involved the whole of the short arm of chromosome 11, in a few tumours allele loss was restricted to band 11p15 or 11p13 and distal sequences. This suggests mutations in two distinct regions play an important role in Wilms' tumorigenesis. There was no apparent correlation between loss of heterozygosity and tumour stage, age of presentation, or prior exposure to chemotherapy.

Reeve AE, Sih SA, Raizis AM, Feinberg AP
Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms' tumor cells.
Mol Cell Biol. 1989; 9(4):1799-803 [PubMed] Free Access to Full Article Related Publications
Children with associated Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) frequently have a cytogenetically visible germ line deletion of chromosomal band 11p13. In accordance with the Knudson hypothesis of two-hit carcinogenesis, the absence of this chromosomal band suggests that loss of both alleles of a gene at 11p13 causes Wilms' tumor. Consistent with this model, chromosomes from sporadically occurring Wilms' tumor cells frequently show loss of allelic heterozygosity at polymorphic 11p15 loci, and therefore it has been assumed that allelic loss extends proximally to include 11p13. We report here that in samples from five sporadic Wilms' tumors, allelic loss occurred distal to the WAGR locus on 11p13. In cells from one tumor, mitotic recombination occurred distal to the gamma-globin gene on 11p15.5. Thus, allelic loss in sporadic Wilms' tumor cells may involve a second locus on 11p.

Koufos A, Grundy P, Morgan K, et al.
Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15.5.
Am J Hum Genet. 1989; 44(5):711-9 [PubMed] Free Access to Full Article Related Publications
Wilms tumor of the kidney occurs with increased frequency in association with two clinically and cytogenetically distinct congenital syndromes, the Wiedemann-Beckwith syndrome (WBS) and the triad of aniridia, genitourinary anomalies, and mental retardation (WAGR). Constitutional deletions in the latter situation and similar alterations in sporadic Wilms tumors have implicated the chromosomal 11p13 region in neoplastic development. In contrast, some sporadic cases of WBS have been reported to have a constitutional duplication of chromosome 11p15. In order to resolve this seeming paradox, we have analyzed a family segregating WBS for linkage to DNA markers mapped to chromosome 11p. Consonant with the cytogenetic alterations in sporadic WBS cases, we obtained evidence for tight linkage of the mutation causing the syndrome to markers located at 11p15.5. Also consistent with this localization, we identified a subset of Wilms tumors, not associated with WBS, which have attained somatic homozygosity through mitotic recombination, with the smallest shared region of overlap being distal to the beta-globin complex at 11p15.5. These data provide evidence that familial WBS likely results from a defect at the same genetic locus as does its sporadic counterpart. Further, the data suggest there is another locus, distinct from that involved in the WAGR syndrome, which plays a role in the association of Wilms tumor with WBS.

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