Wilms Tumour


The vast majority (~95%) of Wilms tumors are sporodic; - not due to inherited genetic alterations, but rather developing as a result of genetic alterations that occur in just a few cells in the body. Familial Wilms' tumour (defined as either bilateral disease or a family history of Wilms' tumour) account for approximately 5% of cases. For those with sporadic (unilateral) disease the risk of Wilms' tumour among their offspring is low: in a series of 179 children from 96 survivors of unilateral Wilms' (Li, 1988) non had developed the disease (upper 95% CI 2%). Children with WAGR Syndrome, Beckwith-Wiedemann Syndrome, Denys-Drash Syndrome Perlman Syndrome and certain other syndromes (below) have an increased risk of Wilms' tumour.

The WT1 gene located at 11p13 was identified in 1989, however, only about a third of patients carry detectable mutations. Thus the development of Wilms' tumour is complex and is likely to involve several other genetic loci. A number of other genes on chromosome 11p have also been implicated in Wilms' tumour, including the putative WT2 gene (11p15). Loci at 1p, 7p, 16q, 17p, and 19q (the putative FWT2 gene) are also implicated.

See also: Wilms' Tumour - clinical resources (11)

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (82)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

WT1 11p13 GUD, AWT1, WAGR, WT33, NPHS4, WIT-2, EWS-WT1 Germline
-WT1 mutation in Wilms Tumour
IGF2 11p15.5 GRDF, IGF-II, PP9974, C11orf43 Imprinting errors
-IGF2 Imprinting and Overexpression in Wilms' Tumour
H19 11p15.5 ASM, BWS, WT2, ASM1, D11S813E, LINC00008, NCRNA00008 -H19 and Wilms Tumour
AMER1 Xq11.2 WTX, OSCS, FAM123B -AMER1 (WTX) mutation in Wilms Tumour
WT2 11p15.5 ADCR, MTACR1 -WT2 and Wilms Tumour
PAX6 11p13 AN, AN2, FVH1, MGDA, WAGR, ASGD5, D11S812E -PAX6 and Wilms Tumour
EGR1 5q31.2 TIS8, AT225, G0S30, NGFI-A, ZNF225, KROX-24, ZIF-268 -EGR1 and Wilms Tumour
DROSHA 5p13.3 RN3, ETOHI2, RNASEN, RANSE3L, RNASE3L, HSA242976 -DROSHA and Wilms Tumour
GPC3 Xq26.2 SGB, DGSX, MXR7, SDYS, SGBS, OCI-5, SGBS1, GTR2-2 -GPC3 expression in Wilms' Tumor
CTCF 16q22.1 MRD21 -CTCF and Wilms Tumour
CTGF 6q23.2 CCN2, NOV2, HCS24, IGFBP8 -CTGF and Wilms Tumour
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 Amplification
-MYCN amplification in Wilms Tumor
IGF1R 15q26.3 IGFR, CD221, IGFIR, JTK13 -IGF1R Overexpression in Wilms' Tumour
FH 1q43 MCL, FMRD, HsFH, LRCC, HLRCC, MCUL1 -FH and Wilms Tumour
NOV 8q24.12 CCN3, NOVh, IBP-9, IGFBP9, IGFBP-9 -NOV and Wilms Tumour
DICER1 14q32.13 DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE -DICER1 and Wilms Tumour
DIS3L2 2q37.1 FAM6A, PRLMNS, hDIS3L2 -DIS3L2 and Wilms Tumour
KCNQ1 11p15.5-p15.4 LQT, RWS, WRS, LQT1, SQT2, ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, Kv1.9, Kv7.1, KVLQT1 -KCNQ1 and Wilms Tumour
CD99 Xp22.33 and Yp11.2 MIC2, HBA71, MIC2X, MIC2Y, MSK5X -CD99 and Wilms Tumour
CITED1 Xq13.1 MSG1 -CITED1 and Wilms Tumour
IGF2R 6q25.3 MPR1, MPRI, CD222, CIMPR, M6P-R, MPR300, CI-M6PR, MPR 300, M6P/IGF2R Germline
Imprinting errors
-IGF2R Imprinting Errors in Wilms' Tumour
DGCR8 22q11.21 Gy1, pasha, DGCRK6, C22orf12 -DGCR8 and Wilms Tumour
KCNQ1OT1 11p15.5 LIT1, Kncq1, KvDMR1, KCNQ10T1, KCNQ1-AS2, KvLQT1-AS, NCRNA00012 -KCNQ1OT1 and Wilms Tumour
HACE1 6q16.3 SPPRS -HACE1 and Wilms Tumour
CDKN2A 9p21.3 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A -CDKN2A Expression in Wilms' Tumour
BIRC5 17q25.3 API4, EPR-1 -BIRC5 and Wilms Tumour
EWSR1 22q12.2 EWS, EWS-FLI1, bK984G1.4 -EWSR1 and Wilms Tumour
EGR2 10q21.3 AT591, CMT1D, CMT4E, KROX20 -EGR2 and Wilms Tumour
SIX1 14q23.1 BOS3, TIP39, DFNA23 -SIX1 and Wilms Tumour
NTRK3 15q25.3 TRKC, GP145-TrkC, gp145(trkC) -NTRK3 and Wilms Tumour
NTRK2 9q21.33 TRKB, trk-B, GP145-TrkB Prognostic
-NTRK2 expression in Wilms Tumour
STIM1 11p15.4 GOK, TAM, TAM1, IMD10, STRMK, D11S4896E -STIM1 and Wilms Tumour
CAST 5q15 BS-17, PLACK -CAST and Wilms Tumour
HDGF 1q23.1 HMG1L2 -HDGF and Wilms Tumour
CALCA 11p15.2 CT, KC, PCT, CGRP, CALC1, CGRP1, CGRP-I -CALCA and Wilms Tumour
MEST 7q32.2 PEG1 -MEST and Wilms Tumour
SMARCA4 19p13.2 BRG1, CSS4, SNF2, SWI2, MRD16, RTPS2, BAF190, SNF2L4, SNF2LB, hSNF2b, BAF190A -SMARCA4 and Wilms Tumour
SLC22A18 11p15.4 HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A -SLC22A18 and Wilms Tumour
RRM1 11p15.4 R1, RR1, RIR1 -RRM1 and Wilms Tumour
RARRES3 11q12.3 RIG1, TIG3, HRSL4, HRASLS4, PLA1/2-3 -RARRES3 and Wilms Tumour
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 mutations in Wilms Tumor
SMARCB1 22q11.23 RDT, CSS3, INI1, SNF5, Snr1, BAF47, MRD15, RTPS1, Sfh1p, hSNFS, SNF5L1, SWNTS1, PPP1R144 -SMARCB1 and Wilms Tumour
G6PD Xq28 G6PD1 -G6PD and Wilms Tumour
ARHGEF1 19q13.2 LSC, GEF1, LBCL2, SUB1.5, P115-RHOGEF -ARHGEF1 and Wilms Tumour
HPRT1 Xq26.2-q26.3 HPRT, HGPRT -HPRT1 and Wilms Tumour
NR0B1 Xp21.2 AHC, AHX, DSS, GTD, HHG, AHCH, DAX1, DAX-1, NROB1, SRXY2 -NR0B1 and Wilms Tumour
ASXL1 20q11.21 MDS, BOPS -ASXL1 and Wilms Tumour
IGF2-AS 11p15.5 PEG8, IGF2AS, IGF2-AS1 -IGF2-AS and Wilms Tumour
LIN28B 6q16.3-q21 CSDD2 -LIN28B and Wilms Tumour
GPX2 14q23.3 GPRP, GPx-2, GI-GPx, GPRP-2, GPx-GI, GSHPx-2, GSHPX-GI -GPX2 and Wilms Tumour
PPP2R1A 19q13.41 MRD36, PP2AA, PR65A, PP2AAALPHA, PP2A-Aalpha -PPP2R1A and Wilms Tumour
PEG10 7q21.3 EDR, HB-1, Mar2, MEF3L, Mart2, RGAG3 -PEG10 and Wilms Tumour
PPP2R1B 11q23.1 PR65B, PP2A-Abeta -PPP2R1B and Wilms Tumour
MNX1 7q36.3 HB9, HLXB9, SCRA1, HOXHB9 -MNX1 and Wilms Tumour
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Wilms Tumour
GLIPR1 12q21.2 GLIPR, RTVP1, CRISP7 -GLIPR1 and Wilms Tumour
MCM2 3q21 BM28, CCNL1, CDCL1, cdc19, D3S3194, MITOTIN -MCM2 and Wilms Tumour
SET 9q34.11 2PP2A, IGAAD, TAF-I, I2PP2A, IPP2A2, PHAPII, TAF-IBETA Overexpression
-SET overexpression in Wilms Tumor?
HOXA11 7p15.2 HOX1, HOX1I, RUSAT1 -HOXA11 and Wilms Tumour
EPHB2 1p36.12 DRT, EK5, ERK, CAPB, Hek5, PCBC, EPHT3, Tyro5, BDPLT22 -EPHB2 and Wilms Tumour
NBN 8q21.3 ATV, NBS, P95, NBS1, AT-V1, AT-V2 -NBN and Wilms Tumour
PEG3 19q13.43 PW1, ZNF904, ZSCAN24, ZKSCAN22 -PEG3 and Wilms Tumour
MOS 8q12.1 MSV -MOS and Wilms Tumour
HOXB4 17q21.32 HOX2, HOX2F, HOX-2.6 -HOXB4 and Wilms Tumour
AKR1C3 10p15.1 DD3, DDX, PGFS, HAKRB, HAKRe, HA1753, HSD17B5, hluPGFS -AKR1C3 and Wilms Tumour
FOXG1 14q12 BF1, BF2, QIN, FKH2, HBF2, HFK1, HFK2, HFK3, KHL2, FHKL3, FKHL1, FKHL2, FKHL3, FKHL4, HBF-1, HBF-2, HBF-3, FOXG1A, FOXG1B, FOXG1C, HBF-G2 -FOXG1 and Wilms Tumour
MYH11 16p13.11 AAT4, FAA4, SMHC, SMMHC -MYH11 and Wilms Tumour
MYOG 1q32.1 MYF4, myf-4, bHLHc3 -MYOG and Wilms Tumour
CACNA1E 1q25.3 BII, CACH6, gm139, Cav2.3, EIEE69, CACNL1A6 Prognostic
-CACNA1E overexpression in Wilms Tumor
HOXD10 2q31.1 HOX4, HOX4D, HOX4E, Hox-4.4 -HOXD10 and Wilms Tumour
KRT8 12q13 K8, KO, CK8, CK-8, CYK8, K2C8, CARD2 -KRT8 and Wilms Tumour
SELL 1q24.2 TQ1, LAM1, LEU8, LNHR, LSEL, CD62L, LYAM1, PLNHR, LECAM1 -SELL and Wilms Tumour
ADAR 1q21.3 DSH, AGS6, G1P1, IFI4, P136, ADAR1, DRADA, DSRAD, IFI-4, K88DSRBP -ADAR and Wilms Tumour
BUB1B 15q15.1 MVA1, SSK1, BUBR1, Bub1A, MAD3L, hBUBR1, BUB1beta -BUB1B and Wilms Tumour
RIN1 11q13.2 -RIN1 and Wilms Tumour
PBX1 1q23.3 CAKUHED -PBX1 and Wilms Tumour
KRT18 12q13.13 K18, CK-18, CYK18 -KRT18 and Wilms Tumour
BUB1 2q14 BUB1A, BUB1L, hBUB1 -BUB1 and Wilms Tumour
CDKN2C 1p32.3 p18, INK4C, p18-INK4C -CDKN2C and Wilms Tumour
RAB25 1q22 CATX-8, RAB11C -RAB25 and Wilms Tumour
PPP2CA 5q31.1 RP-C, PP2Ac, PP2CA, PP2Calpha -PPP2CA and Wilms Tumour
PPP2CB 8p12 PP2CB, PP2Abeta -PPP2CB and Wilms Tumour

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

Conditions and Syndromes Associated With Increased Risk of Wilms Tumor

Beckwith-Wiedemann SyndromeWT211p15.5
Bloom SyndromeBLM15q26.1
Denys-Drash SyndromeWT111p13
Li-Fraumeni SyndromeTP5317p13.1
Perlman SyndromeDIS3L22q37.1
Sotos SyndromeNSD15q35
Simpson-Golabi-Behemel syndromeGPC3Xq26.1
WAGR SyndromeWT111p13

Latest Publications

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.

Phelps HM, Pierce JM, Murphy AJ, et al.
FXR1 expression domain in Wilms tumor.
J Pediatr Surg. 2019; 54(6):1198-1205 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
BACKGROUND/PURPOSE: Wilms tumor (WT) is the most common childhood kidney cancer globally. Our prior unbiased proteomic screen of WT disparities revealed increased expression of Fragile X-Related 1 (FXR1) in Kenyan specimens where survival is dismal. FXR1 is an RNA-binding protein that associates with poor outcomes in multiple adult cancers. The aim of this study therefore was to validate and characterize the FXR1 expression domain in WT.
METHODS: Quantitative FXR1 gene expression was compared between WT, adjacent, adult, and fetal kidney specimens. The cellular and subcellular expression domain of FXR1 was characterized across these tissues using immunoperoxidase staining. RNA-sequencing of FXR1 was performed from WT and other pediatric malignancies to examine its broader target potential.
RESULTS: FXR1 was detected in all clinical WT specimens evaluated (n = 82), and as a result appeared independent of demographic, histology, or adverse event. Specific cytosolic staining was strongest in blastema, intermediate and variable in epithelia, and weakest in stroma. When present, areas of skeletal muscle differentiation stained strongly for FXR1. qPCR revealed increased FXR1 expression in WT compared to adult and adjacent kidney (p < 0.0002) but was similar to fetal kidney (p = 0.648). RNA-sequencing revealed expression of FXR1 in multiple pediatric tumors, greatest in rhabdomyosarcoma and WT.
CONCLUSIONS: FXR1 was expressed consistently across this broad sampling of WT and most robustly in the primitive blastema. Notably, FXR1 labeled a specific self-renewing progenitor population of the fetal kidney.

Sapio MR, Iadarola MJ, LaPaglia DM, et al.
Haploinsufficiency of the brain-derived neurotrophic factor gene is associated with reduced pain sensitivity.
Pain. 2019; 160(5):1070-1081 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
Rare pain-insensitive individuals offer unique insights into how pain circuits function and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, and range of intellectual disabilities) syndrome, who have variably sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ- and C-fiber-mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber-mediated cold responses and cold avoidance on a cold-plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that hemizygous deletion of the BDNF gene reduces pain sensitivity and establishes BDNF as a determinant of nociceptive sensitivity.

Liu K, He B, Xu J, et al.
miR-483-5p Targets MKNK1 to Suppress Wilms' Tumor Cell Proliferation and Apoptosis In Vitro and In Vivo.
Med Sci Monit. 2019; 25:1459-1468 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
BACKGROUND Wilms' tumor (WT) is the most common type of renal tumor in children and it has high mortality rates. MicroRNAs (miRNAs) are important regulators of cellular differentiation processes that have been discovered to contribute to the development of various kinds of tumors. MATERIAL AND METHODS The Wilms' tumor tissues and adjacent tissues were obtained from 28 patients to quantity miR-483-5p expression level. The miR-483-5p mimics and scrambles were transfected into the human kidney WT cell line GHINK-1 to evaluate the effect of miR-483-5p on Wilms' tumor cell proliferation and apoptosis in vitro. A total of 18 female BALB/c nu/nu mice were used to further confirm how miR-483-5p affects Wilms' tumor in vivo. RESULTS In the present study, miR-483-5p was identified to be downregulated in Wilms' tumor tissues compared with the normal adjacent tissues. Additionally, low expression of mir-483-5p was significantly correlated with unfavorable histology subtypes, lymphatic metastasis, and late clinical stage (stage III and IV). Overexpression of miR-483-5p inhibited the proliferation and colony formation of GHINK-1 (Wilms' tumor) cells compared with the control group due to enhanced cell apoptosis. Furthermore, miR-483-5p upregulated the protein expression level of caspase-3. Finally, MAP kinase-interacting serine/threonine-protein kinase 1 was identified as a direct target of miR-483-5p, which was confirmed by luciferase reporter assay and Western blotting. CONCLUSIONS miR-483-5p suppressed WT cell proliferation via inducing apoptosis through targeting MKNK1. This may provide novel insights into the mechanisms underlying WT and a potential therapeutic candidate for the treatment of WT in the future.

Cheng YF, Wang XM, Yan M, Xiao JG
[Expression of the Fra-1 gene in the peripheral blood of children with Wilms tumor].
Zhongguo Dang Dai Er Ke Za Zhi. 2019; 21(2):161-164 [PubMed] Related Publications
OBJECTIVE: To study the expression of the Fra-1 gene in the peripheral blood of children with Wilms tumor and its clinical significance.
METHODS: Fifty children pathologically diagnosed with Wilms tumor between December 2012 and January 2018 were enrolled as the case group, and 40 healthy children for physical examination were selected as the control group. Among the 45 children with Wilms tumor who were followed up, the children with continuous remission were included in the ideal efficacy group (n=33), and those with recurrence, metastasis or death were included in the poor efficacy group (n=12). Peripheral blood samples were collected from all subjects. Quantitative real-time PCR was used to measure the mRNA expression of Fra-1.
RESULTS: The case group had significantly higher mRNA expression of Fra-1 in peripheral blood than the control group (P<0.05). In the case group, Fra-1 mRNA expression was significantly different between the individuals with and without distant metastasis and those with different TNM stages (P<0.05), but was not significantly different between the individuals with different sexes, ages, tumor diabetes, tumor locations and alpha-fetoprotein levels (P>0.05). The mRNA expression of Fra-1 was significantly lower in the ideal efficacy group than in the poor efficacy group (P<0.05).
CONCLUSIONS: Fra-1 may be involved in the development of Wilms tumor and plays a certain role in its development, invasion and metastasis, but the mechanism remains to be further studied.

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] Article available free on PMC after 01/06/2020 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.

Liu P, Zhuo Z, Li W, et al.
Biosci Rep. 2019; 39(1) [PubMed] Article available free on PMC after 01/06/2020 Related Publications
Wilms tumor is the most common renal malignancy that occurs in children.

Jo N, Sogabe Y, Yamada Y, et al.
Platforms of in vivo genome editing with inducible Cas9 for advanced cancer modeling.
Cancer Sci. 2019; 110(3):926-938 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
The emergence of clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology has dramatically advanced how we manipulate the genome. Regarding in vivo experiments, Cas9-transgenic animals could provide efficient and complex genome editing. However, this potential has not been fully realized partly due to a lack of convenient platforms and limited examples of successful disease modeling. Here, we devised two doxycycline (Dox)-inducible Cas9 platforms that efficiently enable conditional genome editing at multiple loci in vitro and in vivo. In these platforms, we took advantage of a site-specific multi-segment cloning strategy for rapid and easy integration of multiple single guide (sg)RNAs. We found that a platform containing rtTA at the Rosa26 locus and TRE-Cas9 together with multiple sgRNAs at the Col1a1 locus showed higher efficiency of inducible insertions and deletions (indels) with minimal leaky editing. Using this platform, we succeeded to model Wilms' tumor and the progression of intestinal adenomas with multiple mutations including an activating mutation with a large genomic deletion. Collectively, the established platform should make complicated disease modeling in the mouse easily attainable, extending the range of in vivo experiments in various biological fields including cancer research.

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] Article available free on PMC after 01/06/2020 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] Article available free on PMC after 01/06/2020 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] Article available free on PMC after 01/06/2020 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

Loke BN, Wong MK, Tawng KD, et al.
Clinical, pathological and loss of heterozygosity differences in Wilms tumors between Asian and non-Asian children.
Int J Cancer. 2019; 144(6):1234-1242 [PubMed] Related Publications
Wilms tumor demonstrates significant interethnic epidemiological, histological and outcome differences, and is rare and poorly studied among Asians. We compared the clinicopathological, and loss of heterozygosity (LOH) profile and survival outcomes of Asian and non-Asian patients with Wilms tumor. Clinical charts and histological slides from patients with malignant renal tumors over a period of 20 years were retrospectively reviewed. We adapted a genotyping assay to determine 1p36 and 16q21-22 LOH in formalin-fixed paraffin-embedded (FFPE) specimens, and compared these characteristics between Asian and non-Asian patients. Fifty-three (79.1%) Asian and 14 (20.9%) non-Asian patients had Wilms tumors. Compared to non-Asians, Asians were younger (mean 4.6 and 4.0 years, respectively), had more equal gender distribution (female: male = 1.8 and 1.0, respectively), fewer tumors with unfavorable histology (25.0% and 4.1%, respectively, p = 0.05), and less advanced disease at presentation, yet similar nodal metastases rates (16.7% and 18.4%, respectively). No Asian patients had bilateral tumors. Our adapted genotyping assay accurately determined LOH in FFPE specimens <10 years post-fixation. Among 30 Asian patients, 1p and 16q LOH were each detected in 5 (16.7%) patients, respectively-similar to rates reported in other ethnicities. Yet after similar treatment with National Wilms Tumor Study regimens, 15-year event-free and overall survival for Asian patients was 95.7% and 96.3% respectively. In summary, despite similar nodal metastasis and LOH rates, Asian patients had fewer unfavorable histology tumors, lower-stage disease, and better survival outcomes. The bases for these differences and implications on treatment strategy for these patients warrant further study.

Sun LZ, Wang HY, Li M, et al.
[Clinical and pathological features and mutational types of WT1 mutation-associated nephropathy].
Zhonghua Er Ke Za Zhi. 2018; 56(10):769-774 [PubMed] Related Publications

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.

Bu Q, He H, Fan D, et al.
Association between loss of heterozygosity of chromosome 16q and survival in Wilms' tumor: A meta-analysis.
Pathol Res Pract. 2018; 214(11):1772-1777 [PubMed] Related Publications
BACKGROUND: Wilms' tumor (WT) is the most common pediatric renal tumor. Despite its high survival rate, the potential prognostic factors should further be studied to reduce the intensity of the treatment. A few studies have found LOH of 16q is associated with worse survival in patients with WT, but it is still contradictory. This study aimed to performed a meta-analysis to clarify this.
METHODS: Databases including the Wanfang, PubMed, Chinese National Knowledge Infrastructure, Embase, and Cochrane Library databases were searched July 2018. The meta-analysis was done using Stata (version 14.0). Publication bias was evaluated by funnel plots, Begg's test, and Egger's test. The trim-and-fill method was applied if significant publication bias existed. Sensitivity analysis was performed to evaluate the stability of the results.
RESULTS: This meta-analysis identified 9 cohort studies encompassing 3266 cases. The pooled relative risk when comparing LOH of 16q groups with control groups was 2.22 [95% confidence interval (CI) = 1.64-3.00, P < 0.001], and the pooled hazard ratio was 1.92 (95%CI = 1.32-2.80, P = 0.001). The results were stable after correcting for publication bias and performing a leave-one-out sensitivity analysis.
CONCLUSIONS: This meta-analysis indicated that LOH of 16q was significantly associated with worse survival in WT. Further studies need to identify this conclusion because the overall quality of the included studies is not high, investigate the impact of LOH of 16q on the survival of WT patients in different subgroups and identify better treatments for WT patients with LOH of 16q in order to lengthen their survival.

Abbo O, Pinnagoda K, Brouchet L, et al.
Wilms tumor, pleuropulmonary blastoma, and DICER1: case report and literature review.
World J Surg Oncol. 2018; 16(1):164 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Pleuroblastoma (PPB) is a rare pediatric tumor which, in 30% of cases, is associated with cystic nephroma. It has been recently linked to the DICER1 mutation as part of a predisposition syndrome for various tumors. However, if DICER 1 anomalies have been reported in patients with Wilms tumor (WT), to date, no cases of PPB, WT, and DICER1 mutations have been reported in the same patient.
CASE PRESENTATION: We report the case of a 3-year-old patient, initially managed for metastatic WT. During his clinical course, the diagnosis of a PPB was made after detecting the DICER1 mutation and subsequent management was therefore modified.
CONCLUSION: This case highlights that in case of simultaneous discovery of a renal tumor and a pulmonary lesion in a child, the DICER 1 mutations should be looked for as these could help adapt management and schedule the surgical procedures.

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

Tang ML, Xiao P, Zou JZ, et al.
[Effect of LINE1-ORF1p overexpression on the proliferation of nephroblastoma WT_CLS1 cells].
Zhongguo Dang Dai Er Ke Za Zhi. 2018; 20(6):501-507 [PubMed] Related Publications
OBJECTIVE: To prepare the LINE1-ORF1p polyclonal antibody, and to study the effect of LINE1-ORF1p on the proliferation of nephroblastoma WT_CLS1 cells.
METHODS: A genetic engineering method was used to achieve prokaryotic expression of LINE1-ORF1p, and rabbits were immunized with LINE1-ORF1p to prepare polyclonal antibody. Indirect ELISA was used to evaluate antibody titer, and Western blot and immunohistochemistry were used to evaluate the specific ability of antibody to recognize LINE1-ORF1p. The eukaryotic expression vector pEGFP-N1-LINE1-ORF1 was constructed and used to transfect WT_CLS1 cells. Western blot and qRT-PCR were used to measure the protein and mRNA expression of LINE1-ORF1, respectively, and cell proliferation assay and colony-forming assay were used to evaluate the effect of LINE1-ORF1p on the proliferation of WT_CLS1 cells and the formation of tumor cell clone.
RESULTS: The LINE1-ORF1p antibody prepared had a titer of >1:16 000 and could specifically recognize LINE1-ORF1p in cells and tumor tissue. WT_CLS1 cells transfected with pEGFP-N1-LINE1-ORF1 had significant increases in the mRNA and protein expression of LINE1-ORF1 and significantly enhanced cell proliferation ability and colony formation ability (P<0.05).
CONCLUSIONS: LINE1-ORF1p can promote the growth of nephroblastoma cells and the formation of tumor cell clone, and may be involved in the pathogenesis of nephroblastoma.

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.

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.

MacFarland SP, Duffy KA, Bhatti TR, et al.
Diagnosis of Beckwith-Wiedemann syndrome in children presenting with Wilms tumor.
Pediatr Blood Cancer. 2018; 65(10):e27296 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Beckwith-Wiedemann syndrome (BWS) is a genetic syndrome associated with overgrowth and cancer predisposition, including predisposition to Wilms tumor (WT). Patients with BWS and BWS spectrum are screened from birth to age 7 years for BWS-associated cancers. However, in some cases a BWS-associated cancer may be the first recognized manifestation of the syndrome. We describe 12 patients diagnosed with BWS after presenting with a WT. We discuss the features of BWS in these patients and hypothesize that earlier detection of BWS by attention to its subtler manifestations could lead to earlier detection of children at risk for associated malignancies.

Jiménez I, Chicard M, Colmet-Daage L, et al.
Circulating tumor DNA analysis enables molecular characterization of pediatric renal tumors at diagnosis.
Int J Cancer. 2019; 144(1):68-79 [PubMed] Related Publications
Circulating tumor DNA (ctDNA) is a powerful tool for the molecular characterization of cancer. The most frequent pediatric kidney tumors (KT) are Wilms' tumors (WT), but other diagnoses may occur. According to the SIOP strategy, in most countries pediatric KT have a presumptive diagnosis of WT if they are clinically and radiologically compatible. The histologic confirmation is established after post-chemotherapy nephrectomy. Thus, there is a risk for a small fraction of patients to receive neoadjuvant chemotherapy that is not adapted to the disease. The aim of this work is to perform molecular diagnosis of pediatric KT by tumor genetic characterization based on the analysis of ctDNA. We analyzed ctDNA extracted from plasma samples of 18 pediatric patients with KT by whole-exome sequencing and compared the results to their matched tumor and germline DNA. Copy number alterations (CNAs) and single nucleotide variations (SNVs) were analyzed. We were able to detect tumor cell specific genetic alterations-CNAs, SNVs or both-in ctDNA in all patients except in one (for whom the plasma sample was obtained long after nephrectomy). These results open the door to new applications for the study of ctDNA with regards to the molecular diagnosis of KT, with a possibility of its usefulness for adapting the treatment early after diagnosis, but also for disease monitoring and follow up.

Halliday BJ, Fukuzawa R, Markie DM, et al.
Germline mutations and somatic inactivation of TRIM28 in Wilms tumour.
PLoS Genet. 2018; 14(6):e1007399 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in TRIM28 predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of TRIM28, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. TRIM28-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of TRIM28 provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.

Zhao H, Zhao H, Zhang Y, Zhou Y
MicroRNA‑199b promotes cell proliferation and invasion in Wilms' tumour by directly targeting Runt‑related transcription factor 3.
Mol Med Rep. 2018; 18(2):1812-1819 [PubMed] Related Publications
Emerging evidence has demonstrated that the deregulation of microRNAs (miRNAs) contributes to Wilms' tumour (WT) malignant progression. Therefore, identifying the essential miRNAs for WT onset and progression may be a promising therapeutic method for patients with this disease. Dysregulation of miRNA‑199b (miR‑199b) serves significant roles in various types of human cancer. However, its expression patterns, possible functions and associated mechanisms in WT are largely unknown. In the present study, the expression of miR‑199b in WT tissues was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis. The biological functions of miR‑199b overexpression in WT cells were determined using Cell counting kit‑8 and Transwell invasion assays. The mechanisms underlying the action of miR‑199b in WT cells were also investigated using bioinformatics analysis, a luciferase reporter assay, RT‑qPCR and western blot analysis. It was revealed that miR‑199b expression was upregulated in WT tissues. In addition, the downregulation of miR‑199b attenuated the proliferation and invasion of WT cells. Runt‑related transcription factor 3 (RUNX3) was mechanistically predicted as a potential target of miR‑199b. Subsequent experiments demonstrated that RUNX3 was a direct target gene of miR‑199b in WT. In addition, the downregulation of RUNX3 in the WT tissues was inversely correlated with the miR‑199b expression level. The recovered RUNX3 expression counteracted the oncogenic roles of miR‑199b in WT cells. Therefore miR‑199b may serve as an oncogene in WT progression by directly targeting RUNX3, thereby suggesting that the miR‑199b/RUNX3 axis may be a promising therapeutic target for patients with WT.

Zhu S, Zhang L, Zhao Z, et al.
MicroRNA‑92a‑3p inhibits the cell proliferation, migration and invasion of Wilms tumor by targeting NOTCH1.
Oncol Rep. 2018; 40(2):571-578 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Dysregulation of miR‑92a‑3p has been shown to contribute to many tumorigenic processes, and is correlated with tumor progression and prognosis. However, the association between miR‑92a‑3p and the clinicopathological features of Wilms tumorand its regulatory mechanism remain unknown. In the present study, we demonstrated that miR‑92a‑3p was downregulated in Wilms tumor tissues and was significantly correlated with the lung metastasis of patients with Wilms tumor. Furthermore, miR‑92a‑3p mimics suppressed Wilms tumor cell proliferation, migration and invasion by in vitro assays. In addition, miR‑92a‑3p knockdown promoted tumor progression. Moreover, miR‑92a‑3p was shown to target directly the 3'‑UTR of NOTCH1 mRNA by Dual‑Luciferase reporter assays in Wilm's tumor cells. miR‑92a‑3p mimics decreased the expression of mRNA and protein of NOTCH1. miR‑92a‑3p inhibitor enhanced NOTCH1 expression by using western blotting and qPCR. In Wilms tumor tissues, NOTCH1 was highly expressed when compared with that in adjacent non‑tumor tissues. NOTCH1 expression was found to be negatively correlated with miR‑92a‑3p in tumor tissues. Knockdown of NOTCH1 expression reversed the promotive effect of miR‑92a‑3p inhibitor on the cell proliferation, migration and invasion in Wilms tumor. In conclusion, miR‑92a‑3p blocks the progression of Wilms tumor by targeting NOTCH1.

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 01/10/2019 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.

Teranishi H, Koga Y, Nakashima K, et al.
Cancer Management in Kabuki Syndrome: The First Case of Wilms Tumor and a Literature Review.
J Pediatr Hematol Oncol. 2018; 40(5):391-394 [PubMed] Related Publications
A 3-year-old Japanese girl treated for hypoplastic left heart syndrome and Dandy-Walker syndrome was diagnosed with Kabuki syndrome (KS) with a mutation of KMT2D; c.13285C>T:p.Q4429*. Concurrently, macrohematuria portended the diagnosis of Wilms tumor. Postoperative chemotherapy has achieved complete remission despite a prolonged and reduced regimen due to liver dysfunction and convulsions. Cancer predisposition has been suggested for KS due to oncogenic mutations in KMT2D or KDM6A. The first case of nephroblastoma exemplified the treatability of malignancies in KS patients, as shown in the 9 cases reviewed. Active screening and intervention are recommended for the cure of malignancy in KS children.

Familial Wilms' Tumour

Hereditary Wilms' tumour (defined as either bilateral disease or a family history of Wilms' tumour) is uncommon. Bonaiti-Pellie and colleagues (1992) analysed family history for 501 Wilms' tumour patients collected by questionnaire and/or interview of parents. Just 12 patients (2.4%) had a positive family history of Wilms' tumour, while 4.6% had bilateral tumours. Other large series of patients enrolled on clinical trials likewise suggest that the heritable fraction of Wilms' tumour is relatively small; (Pastore, 1988 and Breslow, 1982).

Breslow NE, Olson J, Moksness J, et al.
Familial Wilms' tumor: a descriptive study.
Med Pediatr Oncol. 1996; 27(5):398-403 [PubMed] Related Publications
Among 6,209 patients with Wilms' tumor entered on the National Wilms' Tumor Study (NWTS), 93 patients (1.5%) from 63 families had a positive family history. In 30 of these 63 families a (half) sibling or parent of the NWTS patient was confirmed to have had Wilms' tumor. Fifteen (16.1%) of the familial, but only 7.1% of sporadic cases, had bilateral disease. Mean ages at diagnosis were 15.8 vs. 35.2 months (P = 0.012) for bilateral vs. unilateral familial cases and 32.0 vs. 44.7 months for sporadic cases. Intralobar nephrogenic rests were found twice as frequently in association with the tumors of familial as with those of sporadic cases. Cases of bilateral and metastatic disease tended to cluster within specific families, suggesting heterogeneity in the genetic etiology. The number and age distribution of familial cases transmitted through the father were about the same as those of cases transmitted through the mother. This finding is inconsistent with models of genomic imprinting that involve familial transmission of a tumor-suppressor gene and it casts further doubt on the hypothesis that all bilateral cases are hereditary.

Rapley EA, Barfoot R, Bonaïti-Pellié C, et al.
Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2.
Br J Cancer. 2000; 83(2):177-83 [PubMed] Free Access to Full Article Related Publications
Three loci have been implicated in familial Wilms tumour: WT1 located on chromosome 11p13, FWT1 on 17q12-q21, and FWT2 on 19q13. Two out of 19 Wilms tumour families evaluated showed strong evidence against linkage at all three loci. Both of these families contained at least three cases of Wilms tumour indicating that they were highly likely to be due to genetic susceptibility and therefore that one or more additional familial Wilms tumour susceptibility genes remain to be found.

Breslow NE, Beckwith JB
Epidemiological features of Wilms' tumor: results of the National Wilms' Tumor Study.
J Natl Cancer Inst. 1982; 68(3):429-36 [PubMed] Related Publications
Nearly 2,000 children with Wilm's tumor registered in a national clinical trial during 1969-81 showed high rates of aniridia, hemihypertrophy, cryptorchidism, hypospadias, and other genitourinary anomalies. Patients with bilateral disease, who constituted 5% of the total, had younger ages at diagnosis and an increased incidence of congenital anomalies and renal blastemal rests. Those with multicentric unilateral lesions had more blastemal rests but were otherwise indistinguishable from the unicentric cases. The 20 familial cases had none of the features usually associated with genetic tumors: neither younger ages nor an increase in bilaterality nor associated congenital anomalies. These observations suggest that the fraction of Wilm's tumors that is due to an inherited mutation may be substantially smaller than previously supposed and support the concept that the disease arises from a variety of pathogenetic pathways.

Pastore G, Carli M, Lemerle J, et al.
Epidemiological features of Wilms' tumor: results of studies by the International Society of Paediatric Oncology (SIOP).
Med Pediatr Oncol. 1988; 16(1):7-11 [PubMed] Related Publications
This descriptive epidemiology study of 1,040 children with Wilms' tumor (WT) registered in the International Society of Paediatric Oncology (SIOP) clinical trials confirms the findings reported by the National Wilms' Tumor Study. The male:female rate was 0.89:1. The mean age at diagnosis of the 43 bilateral cases was significantly younger than children with unilateral renal involvement (32.4 vs 45 months). However, the mean ages of diagnosis for unilateral multicentric and for unicentric WT were very similar. On the other hand, the mean age at diagnosis of children with sporadic aniridia and hypospadias was younger than the mean age of patients with or without other congenital malformations. Thus aniridia as well as hypospadias could be indices of the first mutation, according to the Knudson and Stron hypothesis. WT was reported in two members of each of five families. However, these familial cases were comparable in terms of demographic and clinical features to the nonfamilial ones. These data suggest that the heritable fraction of WT is relatively small and that genetic and environmental factors interact in the development of WT.

Bonaïti-Pellié C, Chompret A, Tournade MF, et al.
Genetics and epidemiology of Wilms' tumor: the French Wilms' tumor study.
Med Pediatr Oncol. 1992; 20(4):284-91 [PubMed] Related Publications
A complete family history was obtained for 501 patients with Wilms' tumor, treated in departments of pediatric oncology in whole France. The information was collected by self-questionnaire and/or by interview of parents. The proportion of bilateral cases is 4.6% and there are 12 patients (2.4%) with a positive family history of Wilms' tumor. The affected relatives are most often distant and no first degree relative was affected. Apart from the well-known associations with aniridia, hemihypertrophy, genitourinary anomalies, Beckwith-Wiedeemann, and Drash syndromes, there is also a significant excess of congenital heart defects (P = .008) which remains to be explained. Several findings support the bimutational hypothesis such as earlier diagnosis and increased parental age in bilateral cases. No particular anomalies and no increased frequency of childhood cancer were found in patients' relatives. The frequency of Wilms' tumor in relatives was estimated to be less than 0.4% in sibs, 0.06% in uncles and aunts, and 0.04% in first cousins. These figures are very different from those found in retinoblastoma and suggest that the mechanism may be more complex in Wilms' tumor. This conclusion is in agreement with molecular biology studies in tumors and linkage analysis in multiple case families which suggest that more than one locus is involved.

Recurrent Chromosome Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

LOH 19q in Familial Wilms' Tumour (FWT2 19q13.3-q13.4)

McDonald JM, Douglass EC, Fisher R, et al.
Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two-locus model for the etiology of familial tumors.
Cancer Res. 1998; 58(7):1387-90 [PubMed] Related Publications
Familial predisposition to Wilms' tumor (WT), a childhood kidney tumor, is inherited as an autosomal dominant trait. For most WT families studied, the 11p13 gene WT1 and genomic regions implicated in tumorigenesis in a subset of tumors can be ruled out as the site of the familial predisposition gene. Following a genome-wide genetic linkage scan, we have obtained strong evidence (log of the odds ratio = 4.0) in five families for an inherited WT predisposition gene (FWT2) at 19q13.3-q13.4. In addition, we observed loss of heterozygosity at 19q in tumors from individuals from two families in which 19q can be ruled out as the site of the inherited predisposing mutation. From these data, we hypothesize that alterations at two distinct loci are critical rate-limiting steps in the etiology of familial WTs.

LOH 16q in Wilms' Tumour

Klamt B, Schulze M, Thäte C, et al.
Allele loss in Wilms tumors of chromosome arms 11q, 16q, and 22q correlate with clinicopathological parameters.
Genes Chromosomes Cancer. 1998; 22(4):287-94 [PubMed] Related Publications
An extended analysis for loss of heterozygosity (LOH) on eight chromosomes was conducted in a series of 82 Wilms tumors. Observed rates of allele loss were: 9.5% (1p), 5% (4q), 6% (6p), 3% (7p), 9.8% (11q), 28% (11p15), 13.4% (16q), 8.8% (18p), and 13.8% (22q). Known regions of frequent allele loss on chromosome arms 1p, 11p15, and 16q were analyzed with a series of markers, but their size could not be narrowed down to smaller intervals, making any positional cloning effort difficult. In contrast to most previous studies, several tumors exhibited allele loss for multiple chromosomes, suggesting an important role for genome instability in a subset of tumors. Comparison with clinical data revealed a possible prognostic significance, especially for LOH on chromosome arms 11q and 22q with high frequencies of anaplastic tumors, tumor recurrence, and fatal outcome. Similarly, LOH 16q was associated with anaplastic and recurrent tumors. These markers may be helpful in the future for selecting high-risk tumors for modified therapeutic regimens.

Mason JE, Goodfellow PJ, Grundy PE, Skinner MA
16q loss of heterozygosity and microsatellite instability in Wilms' tumor.
J Pediatr Surg. 2000; 35(6):891-6; discussion 896-7 [PubMed] Related Publications
BACKGROUND/PURPOSE: Wilms' tumor is the most common renal malignancy of childhood. Loss of heterozygosity (LOH) at 16q is seen in about 17% of cases and has been associated with a poor prognosis. To more precisely define the pattern of 16q deletion exhibited by Wilms' tumor, the authors performed a detailed LOH analysis of 96 specimens using polymorphic microsatellite repeat markers. The authors also evaluated the neoplasms for the presence of microsatellite instability (MSI).
METHODS: A total of 96 DNA samples were studied using polymerase chain reaction-based LOH analyses amplifying polymorphic microsatellite repeat markers. Screening for MSI using 2 additional genetic markers also was carried out.
RESULTS: The authors found 16q LOH in 14 of the specimens evaluated. Comprehensive analysis of these LOH-positive specimens showed a region of loss spanning 16p11.2-q22.1 and a separate distal region of LOH at 16q23.2-24.2. The distal region of deletion is very small, estimated to be approximately 2.4 megabases. In addition to the observed LOH, 2 specimens were found to consistently exhibit MSI, which has not been reported previously in Wilms' tumor.
CONCLUSIONS: The smallest consensus region of deletion in our analysis of Wilms' tumor 16q LOH measures 2.4 megabases at 16q23.2-q24.2. Additionally, MSI was present in a subset of tumor specimens suggesting that defects in DNA mismatch repair may contribute to the pathogenesis of Wilms' tumor.

Grundy PE, Telzerow PE, Breslow N, et al.
Loss of heterozygosity for chromosomes 16q and 1p in Wilms' tumors predicts an adverse outcome.
Cancer Res. 1994; 54(9):2331-3 [PubMed] Related Publications
We have prospectively analyzed Wilms' tumors from 232 patients registered on the National Wilms' Tumor Study for loss of heterozygosity (LOH) on chromosomes 11p, 16q, and 1p. These chromosomal aberrations were found in 70 (33%), 35 (17%), and 21 (12%) of the informative cases, respectively. LOH for two of these regions occurred in only 25 cases, and only one tumor harbored LOH at all three sites. There was no statistically significant association between LOH at any of the three regions and either the stage or histological classification of the tumor. Patients with tumor-specific LOH for chromosome 16q had relapse rates 3.3 times higher (P = 0.01) and mortality rates 12 times higher (P < 0.01) than patients without LOH for chromosome 16q. These differences remained when adjusted for histology or for stage. Patients with LOH for chromosome 1p had relapse and mortality rates three times higher than those for patients without LOH for chromosome 1p, but these results were not statistically significant. In contrast, LOH for chromosome 11p had no effect on measures of outcome. These molecular markers may serve to further stratify Wilms' tumor patients into biologically favorable and unfavorable subgroups, allowing continued use of the clinical trial mechanism in the study of Wilms' tumor.

Grundy RG, Pritchard J, Scambler P, Cowell JK
Loss of heterozygosity on chromosome 16 in sporadic Wilms' tumour.
Br J Cancer. 1998; 78(9):1181-7 [PubMed] Free Access to Full Article Related Publications
To establish whether loss of heterozygosity (LOH) for chromosome 16q in Wilms' tumours confers an adverse prognosis, DNA from 40 Wilms' tumour/normal pairs were analysed using highly polymorphic microsatellite markers along the length of 16q. Fifteen per cent of tumours showed LOH for 16q. Although the common region of allele loss spanned the 16q24-qter region, a second distinct region of LOH was identified in 16q21. Five out of six tumours showing LOH were either (1) high stage or (2) low stage with unfavourable histology. In addition, there was a higher mortality rate in patients showing LOH for 16q than those that did not. These data strongly support the suggestion that LOH for 16q is associated with an adverse prognosis.

Skotnicka-Klonowicz G, Rieske P, Bartkowiak J, et al.
16q heterozygosity loss in Wilms' tumour in children and its clinical importance.
Eur J Surg Oncol. 2000; 26(1):61-6 [PubMed] Related Publications
INTRODUCTION: The loss of heterozygosity (LOH) of 16q is a structural change detected in about 20-30% of Wilms' tumour cases. Aberrations which result in deletion of 16q are also found in breast cancer, prostate cancer and liver cancer, where they are connected with a worse prognosis. The hypothesis of a bad prognosis in nephroblastomas with LOH 16q was first formulated by scientists from NWTS (National Wilms Tumor Study) on the basis of 232 cases of Wilms' tumour. However, SIOP studies (International Society of Paediatric Oncology) which included 28 cases of Wilms' tumour, did not show any clinico-pathological correlations with LOH 16q. Therefore, we aimed to evaluate the importance of LOH 16q in relation to clinico-pathological factors in a group of children, treated according to the SIOP criteria.
AIMS: The aim of this work was to evaluate the frequency of LOH 16q in sporadic unilateral Wilms' tumour and to study the relationship between LOH 16q and selected patho-clinical parameters. The study comprised 66 children (31 girls and 35 boys) aged from 2 days to 13 years.
METHODS: LOH 16q was studied by the examination of polymorphism of marker sequences in the region 16q24. DNA was isolated from paraffin sections of tissue for routine microscopic examination by the microdissection method. The method of study involved the amplification of polymorphic sequences from the 16q24 region by polymerase chain reaction (PCR) and separation of the products of amplification by polyacrylamide gel electrophoresis. The results were the subject of statistical analysis in relation to gender, age of child at first diagnosis, stage of clinical advancement and histological type of tumour. The connection between LOH 16q and recurrences, metastases and death, and failure free survival and absolute survival of children followed-up for over 24 months after nephrectomy were studied.
RESULTS: The study revealed a lack of correlation between LOH 16q and gender, however LOH 16q was more frequent in children with Wilms' tumour aged >24 months, P<0.05. Also, LOH 16q was more frequent in tumours classified as clinical stage (CS) II or III than in CS I, P<0.05, but there were no differences in the occurrence of LOH 16q in tumours classified as CS II and CS III. We have found no correlation between LOH 16q and the histological type of tumour. However, LOH 16q has been found three times as frequently in tumours from children who died than in tumours of children who survived, P<0.0024.

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