Wilms Tumour

Overview

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

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

Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (77)

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'.

GeneLocationAliasesNotesTopicPapers
WT1 11p13 GUD, AWT1, WAGR, WT33, NPHS4, WIT-2, EWS-WT1 Germline
-WT1 mutation in Wilms Tumour
511
IGF2 11p15.5 IGF-II, PP9974, C11orf43 Imprinting errors
-IGF2 Imprinting and Overexpression in Wilms' Tumour
91
H19 11p15.5 ASM, BWS, WT2, ASM1, PRO2605, D11S813E, LINC00008, NCRNA00008 -H19 and Wilms Tumour
61
AMER1 Xq11.2 WTX, OSCS, FAM123B -AMER1 (WTX) mutation in Wilms Tumour
43
WT2 11p15.5 ADCR, MTACR1 -WT2 and Wilms Tumour
31
PAX6 11p13 AN, AN2, FVH1, MGDA, WAGR, D11S812E -PAX6 and Wilms Tumour
29
EGR1 5q31.1 TIS8, AT225, G0S30, NGFI-A, ZNF225, KROX-24, ZIF-268 -EGR1 and Wilms Tumour
14
CTCF 16q21-q22.3 MRD21 -CTCF and Wilms Tumour
11
IGF1R 15q26.3 IGFR, CD221, IGFIR, JTK13 -IGF1R Overexpression in Wilms' Tumour
10
CTGF 6q23.1 CCN2, NOV2, HCS24, IGFBP8 -CTGF and Wilms Tumour
10
NOV 8q24.1 CCN3, NOVh, IBP-9, IGFBP9, IGFBP-9 -NOV and Wilms Tumour
9
GPC3 Xq26.1 SGB, DGSX, MXR7, SDYS, SGBS, OCI-5, SGBS1, GTR2-2 -GPC3 expression in Wilms' Tumor
8
DROSHA 5p13.3 RN3, ETOHI2, RNASEN, RANSE3L, RNASE3L, HSA242976 -DROSHA and Wilms Tumour
8
FH 1q42.1 MCL, FMRD, LRCC, HLRCC, MCUL1 -FH and Wilms Tumour
8
MYCN 2p24.3 NMYC, ODED, MODED, N-myc, bHLHe37 Amplification
-MYCN amplification in Wilms Tumor
8
CD99 Xp22.32 and Yp11.3 MIC2, HBA71, MIC2X, MIC2Y, MSK5X -CD99 and Wilms Tumour
7
DIS3L2 2q37.1 FAM6A, PRLMNS, hDIS3L2 -DIS3L2 and Wilms Tumour
7
IGF2R 6q26 MPR1, MPRI, CD222, CIMPR, M6P-R Germline
Imprinting errors
-IGF2R Imprinting Errors in Wilms' Tumour
7
KCNQ1 11p15.5 LQT, RWS, WRS, LQT1, SQT2, ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, Kv1.9, Kv7.1, KVLQT1 -KCNQ1 and Wilms Tumour
6
CITED1 Xq13.1 MSG1 -CITED1 and Wilms Tumour
6
BIRC5 17q25 API4, EPR-1 -BIRC5 and Wilms Tumour
5
CDKN2A 9p21 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
5
HACE1 6q16.3 -HACE1 and Wilms Tumour
5
KCNQ1OT1 11p15 LIT1, KvDMR1, KCNQ10T1, KCNQ1-AS2, KvLQT1-AS, NCRNA00012 -KCNQ1OT1 and Wilms Tumour
5
EGR2 10q21.1 AT591, CMT1D, CMT4E, KROX20 -EGR2 and Wilms Tumour
4
NTRK3 15q25 TRKC, gp145(trkC) -NTRK3 and Wilms Tumour
3
STIM1 11p15.5 GOK, TAM, TAM1, IMD10, STRMK, D11S4896E -STIM1 and Wilms Tumour
3
NTRK2 9q22.1 TRKB, trk-B, GP145-TrkB Prognostic
-NTRK2 expression in Wilms Tumour
3
DICER1 14q32.13 DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE -DICER1 and Wilms Tumour
3
SMARCB1 22q11.23 RDT, INI1, SNF5, Snr1, BAF47, MRD15, RTPS1, Sfh1p, hSNFS, SNF5L1, SWNTS1, PPP1R144 -SMARCB1 and Wilms Tumour
2
G6PD Xq28 G6PD1 -G6PD and Wilms Tumour
2
HPRT1 Xq26.1 HPRT, HGPRT -HPRT1 and Wilms Tumour
2
NR0B1 Xp21.3 AHC, AHX, DSS, GTD, HHG, AHCH, DAX1, DAX-1, NROB1, SRXY2 -NR0B1 and Wilms Tumour
2
IGF2-AS 11p15.5 PEG8, IGF2AS, IGF2-AS1 -IGF2-AS and Wilms Tumour
2
FBXW7 4q31.3 AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 -FBXW7 mutations in Wilms Tumor
2
PPP2CB 8p12 PP2CB, PP2Abeta -PPP2CB and Wilms Tumour
2
CAST 5q15 BS-17, PLACK -CAST and Wilms Tumour
2
HDGF 1q23.1 HMG1L2 -HDGF and Wilms Tumour
2
CALCA 11p15.2 CT, KC, CGRP, CALC1, CGRP1, CGRP-I -CALCA and Wilms Tumour
2
PPP2CA 5q31.1 RP-C, PP2Ac, PP2CA, PP2Calpha -PPP2CA and Wilms Tumour
2
MEST 7q32 PEG1 -MEST and Wilms Tumour
2
SLC22A18 11p15.5 HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A -SLC22A18 and Wilms Tumour
2
RRM1 11p15.5 R1, RR1, RIR1 -RRM1 and Wilms Tumour
2
RARRES3 11q23 RIG1, TIG3, HRSL4, HRASLS4, PLA1/2-3 -RARRES3 and Wilms Tumour
2
MOS 8q11 MSV -MOS and Wilms Tumour
1
HOXB4 17q21.32 HOX2, HOX2F, HOX-2.6 -HOXB4 and Wilms Tumour
1
AKR1C3 10p15-p14 DD3, DDX, PGFS, HAKRB, HAKRe, HA1753, HSD17B5, hluPGFS -AKR1C3 and Wilms Tumour
1
FOXG1 14q13 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
1
MNX1 7q36 HB9, HLXB9, SCRA1, HOXHB9 -MNX1 and Wilms Tumour
1
MYOG 1q31-q41 MYF4, myf-4, bHLHc3 -MYOG and Wilms Tumour
1
CACNA1E 1q25.3 BII, CACH6, Cav2.3, CACNL1A6 Prognostic
-CACNA1E overexpression in Wilms Tumor
1
HOXD10 2q31.1 HOX4, HOX4D, HOX4E, Hox-4.4 -HOXD10 and Wilms Tumour
1
ARHGEF1 19q13.13 LSC, GEF1, LBCL2, SUB1.5, P115-RHOGEF -ARHGEF1 and Wilms Tumour
1
PEG10 7q21 EDR, HB-1, Mar2, MEF3L, Mart2, RGAG3 -PEG10 and Wilms Tumour
1
KRT8 12q13 K8, KO, CK8, CK-8, CYK8, K2C8, CARD2 -KRT8 and Wilms Tumour
1
SELL 1q23-q25 TQ1, LAM1, LEU8, LNHR, LSEL, CD62L, LYAM1, PLNHR, LECAM1 -SELL and Wilms Tumour
1
HOXA11 7p15.2 HOX1, HOX1I -HOXA11 and Wilms Tumour
1
RIN1 11q13.2 -RIN1 and Wilms Tumour
1
PBX1 1q23 -PBX1 and Wilms Tumour
1
BUB1 2q14 BUB1A, BUB1L, hBUB1 -BUB1 and Wilms Tumour
1
NBN 8q21 ATV, NBS, P95, NBS1, AT-V1, AT-V2 -NBN and Wilms Tumour
1
RAB25 1q22 CATX-8, RAB11C -RAB25 and Wilms Tumour
1
SIX1 14q23.1 BOS3, TIP39, DFNA23 -SIX1 and Wilms Tumour
1
MYH11 16p13.11 AAT4, FAA4, SMHC, SMMHC -MYH11 and Wilms Tumour
1
LIN28B 6q21 CSDD2 -LIN28B and Wilms Tumour
1
GPX2 14q24.1 GPRP, GPx-2, GI-GPx, GPRP-2, GPx-GI, GSHPx-2, GSHPX-GI -GPX2 and Wilms Tumour
1
PPP2R1A 19q13.41 PR65A, PP2AAALPHA, PP2A-Aalpha -PPP2R1A and Wilms Tumour
1
PPP2R1B 11q23.2 PR65B, PP2A-Abeta -PPP2R1B and Wilms Tumour
1
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Wilms Tumour
1
GLIPR1 12q21.2 GLIPR, RTVP1, CRISP7 -GLIPR1 and Wilms Tumour
1
BUB1B 15q15 MVA1, SSK1, BUBR1, Bub1A, MAD3L, hBUBR1, BUB1beta -BUB1B and Wilms Tumour
1
SMARCA4 19p13.2 BRG1, SNF2, SWI2, MRD16, RTPS2, BAF190, SNF2L4, SNF2LB, hSNF2b, BAF190A -SMARCA4 and Wilms Tumour
1
MCM2 3q21 BM28, CCNL1, CDCL1, cdc19, D3S3194, MITOTIN -MCM2 and Wilms Tumour
1
SET 9q34 2PP2A, IGAAD, TAF-I, I2PP2A, IPP2A2, PHAPII, TAF-IBETA Overexpression
-SET overexpression in Wilms Tumor?
1
CDKN2C 1p32 p18, INK4C, p18-INK4C -CDKN2C and Wilms Tumour
1
EPHB2 1p36.1-p35 DRT, EK5, ERK, CAPB, Hek5, PCBC, EPHT3, Tyro5 -EPHB2 and Wilms Tumour
1
KRT18 12q13 K18, CYK18 -KRT18 and Wilms Tumour
1

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

DiseaseGene(s)LocationNotes
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

Hohenstein P, Pritchard-Jones K, Charlton J
The yin and yang of kidney development and Wilms' tumors.
Genes Dev. 2015; 29(5):467-82 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Wilms' tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms' tumor in the context of renal development. Many of the genes implicated in Wilms' tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general-and specific miRNAs in particular-in normal kidney development that still await further analysis. The recent identification of Wilms' tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions.

Kaneko Y, Okita H, Haruta M, et al.
A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan, and the penetrance rates in children with WT1 germline mutation.
Br J Cancer. 2015; 112(6):1121-33 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
BACKGROUND: Bilateral Wilms tumours (BWTs) occur by germline mutation of various predisposing genes; one of which is WT1 whose abnormality was reported in 17-38% of BWTs in Caucasians, whereas no such studies have been conducted in East-Asians. Carriers with WT1 mutations are increasing because of improved survival.
METHODS: Statuses of WT1 and IGF2 were examined in 45 BWTs from 31 patients with WT1 sequencing and SNP array-based genomic analyses. The penetrance rates were estimated in WT1-mutant familial Wilms tumours collected from the present and previous studies.
RESULTS: We detected WT1 abnormalities in 25 (81%) of 31 patients and two families, which were included in the penetrance rate analysis of familial Wilms tumour. Of 35 BWTs from the 25 patients, 31 had small homozygous WT1 mutations and uniparental disomy of IGF2, while 4 had large 11p13 deletions with the retention of 11p heterozygosity. The penetrance rate was 100% if children inherited small WT1 mutations from their fathers, and 67% if inherited the mutations from their mothers, or inherited or had de novo 11p13 deletions irrespective of parental origin (P=0.057).
CONCLUSIONS: The high incidence of WT1 abnormalities in Japanese BWTs sharply contrasts with the lower incidence in Caucasian counterparts, and the penetrance rates should be clarified for genetic counselling of survivors with WT1 mutations.

Wegert J, Ishaque N, Vardapour R, et al.
Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors.
Cancer Cell. 2015; 27(2):298-311 [PubMed] Related Publications
Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA.

Walz AL, Ooms A, Gadd S, et al.
Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors.
Cancer Cell. 2015; 27(2):286-97 [PubMed] Related Publications
We report the most common single-nucleotide substitution/deletion mutations in favorable histology Wilms tumors (FHWTs) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPGs) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.

Somasundaram A, Ardanowski N, Opalak CF, et al.
Wilms tumor 1 gene, CD97, and the emerging biogenetic profile of glioblastoma.
Neurosurg Focus. 2014; 37(6):E14 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is the most common type of primary brain tumor, and current treatment regimens are only marginally effective. One of the most vexing and malignant aspects of GBM is its pervasive infiltration into surrounding brain tissue. This review describes the role of the Wilms tumor 1 gene (WT1) and its relationship to GBM. WT1 has several alternative splicing products, one of which, the KTS(+) variant, has been demonstrated to be involved in the transcriptional activation of a variety of oncogenes as well as the inhibition of tumor suppressor genes. Further, this paper will examine the relationship of WT1 with CD97, a gene that codes for an epidermal growth factor receptor family member, an adhesion G-protein-coupled receptor, thought to promote tumor invasiveness and migration. The authors suggest that further research into WT1 and CD97 will allow clinicians to begin to deal more effectively with the infiltrative behavior displayed by GBM and design new therapies that target this deadly disease.

Malric A, Defachelles AS, Leblanc T, et al.
Fanconi anemia and solid malignancies in childhood: a national retrospective study.
Pediatr Blood Cancer. 2015; 62(3):463-70 [PubMed] Related Publications
BACKGROUND: Fanconi anemia (FA) predisposes to hematologic disorders and myeloid neoplasia in childhood and to solid cancers, mainly oral carcinomas, in early adulthood. Few cases of solid cancers have been reported in childhood.
PROCEDURES: We conducted a national retrospective study of solid tumors occurring in patients registered with or determined to have FA during childhood in France. Phenotypic features, tumor type, cancer treatment, and outcome were analyzed. Whenever available, fresh-frozen tumors were analyzed by microarray-based comparative genomics hybridization.
RESULTS: We identified eight patients with FA with solid tumor from 1986 to 2012. For two patients, the diagnosis of FA was unknown at the time of cancer diagnosis. Moreover, we identified one fetus with a brain tumor. All patients showed failure to thrive and had dysmorphic features and abnormal skin pigmentation. Seven patients had BRCA2/FANCD1 mutations; five of these featured more than one malignancy and the median age at the time of cancer diagnosis was 11 months (range 0.4-3 years). Solid tumor types included five nephroblastomas, two rhabdomyosarcomas, two neuroblastomas, and three brain tumors. Two children died from the toxic effects of chemotherapy, two patients from the cancer, and one patient from secondary leukemia. Only one BRCA2 patient was alive more than 3 years after diagnosis, after tailored chemotherapy.
CONCLUSION: Solid tumors are rare in FA during childhood, except in patients with BRCA2/FANCD1 mutations. The proper genetic diagnosis is mandatory to tailor the treatment.

Maschietto M, Williams RD, Chagtai T, et al.
TP53 mutational status is a potential marker for risk stratification in Wilms tumour with diffuse anaplasia.
PLoS One. 2014; 9(10):e109924 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
PURPOSE: The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information.
PATIENTS AND METHODS: We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n = 32) and gene expression (n = 36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling.
RESULTS: From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n = 25) had an increased risk of recurrence as a first event (p = 0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p = 0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p = 0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes.
CONCLUSION: This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker.

Li Y, Wang J, Li X, et al.
Role of the Wilms' tumor 1 gene in the aberrant biological behavior of leukemic cells and the related mechanisms.
Oncol Rep. 2014; 32(6):2680-6 [PubMed] Related Publications
The Wilms' tumor 1 (WT1) gene is one of the regulating factors in cell proliferation and development. It is a double-functional gene: an oncogene and a tumor suppressor. This gene was found to be highly expressed in many leukemic cell lines and in patients with acute myeloid leukemia. In the present study, we demonstrated that the WT1 gene was commonly expressed in leukemic cell lines apart from U937 cells. The K562 cell line which expresses WT1 at a high level (mRNA and protein) was used in the entire experiment. By MTT and colony formation assays, we found that curcumin, an inhibitor of the WT1 protein, inhibited cell proliferation and clonogenicity in a time- and dose-dependent manner. It also caused cell cycle arrest at the G2/M phase. We then designed specific short hairpin RNAs (shRNAs) which could downregulate WT1 by 70-80% at the mRNA and protein levels. Reduction in the WT1 levels attenuated the proliferative ability and clonogenicity. Cell cycle progression analysis indicated that the proportion of cells in the G0/G1 phase increased while the proportion in the S phase decreased distinctively. ChIP-DNA selection and ligation (DSL) experiment identified a cohort of genes whose promoters are targeted by WT1. These genes were classified into different cellular signaling pathways using MAS software and included the Wnt/β-catenin pathway, MAPK signaling pathway, apoptosis pathway, and the cell cycle. We focused on the Wnt/β-catenin signaling pathway, and compared expression of several genes in the K562 cells transfected with the control shRNA and WT1-specific shRNA. β-catenin, an important gene in the Wnt canonical pathway, was downregulated after WT1 RNAi. Target genes of β-catenin which participate in cell proliferation and cell cycle regulation, such as CCND1 and MYC, were also significantly downregulated. Collectively, these data suggest that WT1 functions as an oncogene in leukemia cells, and one important mechanism is regulation of the Wnt/β-catenin pathway.

Rakheja D, Chen KS, Liu Y, et al.
Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours.
Nat Commun. 2014; 2:4802 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
Wilms tumour is the most common childhood kidney cancer. Here we report the whole-exome sequencing of 44 Wilms tumours, identifying missense mutations in the microRNA (miRNA)-processing enzymes DROSHA and DICER1, and novel mutations in MYCN, SMARCA4 and ARID1A. Examination of tumour miRNA expression, in vitro processing assays and genomic editing in human cells demonstrates that DICER1 and DROSHA mutations influence miRNA processing through distinct mechanisms. DICER1 RNase IIIB mutations preferentially impair processing of miRNAs deriving from the 5'-arm of pre-miRNA hairpins, while DROSHA RNase IIIB mutations globally inhibit miRNA biogenesis through a dominant-negative mechanism. Both DROSHA and DICER1 mutations impair expression of tumour-suppressing miRNAs, including the let-7 family, important regulators of MYCN, LIN28 and other Wilms tumour oncogenes. These results provide new insights into the mechanisms through which mutations in miRNA biogenesis components reprogramme miRNA expression in human cancer and suggest that these defects define a distinct subclass of Wilms tumours.

Charlton J, Williams RD, Weeks M, et al.
Methylome analysis identifies a Wilms tumor epigenetic biomarker detectable in blood.
Genome Biol. 2014; 15(8):434 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
BACKGROUND: Wilms tumor is the most common pediatric renal malignancy and there is a clinical need for a molecular biomarker to assess treatment response and predict relapse. The known mutated genes in this tumor type show low mutation frequencies, whereas aberrant methylation at 11p15 is by far the most common aberration. We therefore analyzed the epigenome, rather than the genome, to identify ubiquitous tumor-specific biomarkers.
RESULTS: Methylome analysis of matched normal kidney and Wilms tumor identifies 309 preliminary methylation variable positions which we translate into three differentially methylated regions (DMR) for use as tumor-specific biomarkers. Using two novel algorithms we show that these three DMRs are not confounded by cell type composition. We further show that these DMRs are not methylated in embryonic blastema but are intermediately methylated in Wilms tumor precursor lesions. We validate the biomarker DMRs using two independent sample sets of normal kidney and Wilms tumor and seven Wilms tumor histological subtypes, achieving 100% and 98% correct classification, respectively. As proof-of-principle for clinical utility, we successfully use biomarker DMR-2 in a pilot analysis of cell-free circulating DNA to monitor tumor response during treatment in ten patients.
CONCLUSIONS: These findings define the most common methylated regions in Wilms tumor known to date which are not associated with their embryonic origin or precursor stage. We show that this tumor-specific methylated DNA is released into the blood circulation where it can be detected non-invasively showing potential for clinical utility.

Hanks S, Perdeaux ER, Seal S, et al.
Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour.
Nat Commun. 2014; 5:4398 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
Wilms tumour is a childhood kidney cancer. Here we identify inactivating CTR9 mutations in 3 of 35 Wilms tumour families, through exome and Sanger sequencing. By contrast, no similar mutations are present in 1,000 population controls (P<0.0001). Each mutation segregates with Wilms tumour in the family and a second mutational event is present in available tumours. CTR9 is a key component of the polymerase-associated factor 1 complex which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency. These data establish CTR9 as a Wilms tumour predisposition gene and suggest it acts as a tumour suppressor gene.

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

Pasupuleti SK, Katari V, Lokanathan S, et al.
Novel frame shift mutations ('A' deletion) observed in exon 9 of Wilms' tumor (WT1) gene in a patient reported with glomerulosclerosis.
Gene. 2014; 546(1):63-7 [PubMed] Related Publications
Wilms' tumor-suppressor gene-1 (WT1) is a transcription factor that contains four zinc-finger motifs at the C-terminus and plays a crucial role in kidney and gonad development. We have identified primitive glomeruloid formation using immunohistochemistry in a patient who was clinically diagnosed with a Wilms' tumor. In order to understand the involvement of mutations in the WT1 gene, the genomic DNA was isolated from peripheral blood of the patient (18/F). Exon 9 of the WT1 gene was amplified and sequenced. The obtained sequence was BLAST searched against the transcript variants (TV) of the WT1 gene. An amplified exon 9 sequence of the WT1 gene showing similarity with exon 9 of TV-A, F and exon 10 of TV-B, D and E with a deletion of single nucleotide 'A' causing frame shift in the 4th zinc finger domain of the WT1 protein resulted in Wilms' tumor condition. The deletion position is variable with different transcript variants and they are present at: for TV-A c.1592delA, p.468, for TV-F c.1053delA, p.259, for TV-B c.1643delA, p.485, for TV-D c.1652 delA, p.488, and for TV-E c.1095delA, p.273; all these variations resulted in frame shift mutation. In order to substantiate these results in silico analysis was carried out; the structural superimposition of wild type and mutant WT1 structures showed that the mutated region exhibited a different confirmation with RMSD of 1.759Å. Therefore, these results conclusively explain the mutation in the WT1 gene that leads to structural changes contributing to glomerulosclerosis.

Hohenstein P, Hastie ND
LINking microRNAs, kidney development, and Wilms tumors.
Genes Dev. 2014; 28(9):923-5 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
In this issue of Genes & Development, Urbach and colleagues (pp. 971-982) provide compelling data suggesting a role for LIN28 in the pathogenesis of a significant percentage of Wilms tumors. These data extend our insights in the genetics underlying Wilms tumor development and emphasize the importance of stemness and microRNA-mediated processes in the origins of these tumors.

Urbach A, Yermalovich A, Zhang J, et al.
Lin28 sustains early renal progenitors and induces Wilms tumor.
Genes Dev. 2014; 28(9):971-82 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis.

Valind A, Pal N, Asmundsson J, et al.
Confined trisomy 8 mosaicism of meiotic origin: a rare cause of aneuploidy in childhood cancer.
Genes Chromosomes Cancer. 2014; 53(7):634-8 [PubMed] Related Publications
Whether chromosome abnormalities observed in tumor cells may in some cases reflect low-grade somatic mosaicism for anomalies present already at zygote formation, rather than acquired somatic mutations, has for long remained a speculation. We here report a patient with Wilms tumor, where constitutional somatic mosaicism of trisomy 8 was detected in a previously healthy 2 ½-year-old boy. Single Nucleotide Polymorphism (SNP) array analysis of tumor tissue revealed a complex distribution of allele frequencies for chromosome 8 that could not be explained solely by mitotic events. Combined analysis of allele frequencies, chromosome banding, and fluorescence in situ hybridization revealed that the majority of tumor cells contained four copies of chromosome 8, with three distinct haplotypes at a 2:1:1 ratio. Because the patient had not been subject to organ transplantation, these findings indicated that the tumor karyotype evolved from a cell with trisomy 8 of meiotic origin, with subsequent somatic gain of one additional chromosome copy. Haplotype analysis was consistent with trisomy 8 through nondisjunction at meiosis I. Matched normal renal tissue or peripheral blood did not contain detectable amounts of cells with trisomy 8, consistent with the complete lack of mosaic trisomy 8 syndrome features in the patient. This case provides proof of principle for the hypothesis that tumor genotypes may in rare cases reflect meiotic rather than mitotic events, also in patients lacking syndromic features. © 2014 Wiley Periodicals, Inc.

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

Li HJ, Chen YX, Wang Q, Zhang YG
S100A4 mRNA as a prognostic marker and therapeutic target in Wilms tumor (WT).
Eur Rev Med Pharmacol Sci. 2014; 18(6):817-27 [PubMed] Related Publications
OBJECTIVE: Recent studies showed that the S100A4 is candidate prognostic marker or therapeutic targets in cancers. In this study, we first evaluate the expression of S100A4 mRNA in Wilms tumor (WT) and its relationship to the clinicopathological parameters and prognosis. We then tested a hypothesis that the S100A4 gene plays a role in cell proliferation, apoptosis, invasiveness and capillary network formation and regression of established orthotopic tumors of human WT cells.
MATERIALS AND METHODS: Expression of V S100A4 mRNA was examined in 48 surgical specimens of WTs by Quatitive Reverse transcription-PCR analysis (Q-PCR). Correlation between the expression of S100A4 mRNA and clinicopathological parameters was analyzed. We used in vitro and vivo experiments with RNA interference to evaluate the functional role of S100A4 and its potential as a therapeutic target for WT.
RESULTS: S100A4 mRNA levels were significantly higher in carcinoma specimens than in non neoplastic tissues. S100A4 mRNA expression was significantly correlated with tumor size, vascular invasion, node metastasis and tumor stage. We observed that shRNA-mediated suppression of the S100A4 gene significantly promoted apoptosis and reduced the proliferative and invasive capability, angiogenesis of the WT cells SK-NEP-1 in vitro. S100A4-shRNA-transfected cells exhibited a reduced rate of tumor growth under in vivo conditions. Microvascular density (MVD) was reduced by 62% due to S100A4-shRNA treatment (p < 0.01).
CONCLUSIONS: Our present results suggest that S100A4 mRNA plays an important role in the development of WT. It might be useful in evaluating the outcome of patients with WT. S100A4 may be a promising therapeutic target for WT.

Klein S, Lee H, Ghahremani S, et al.
Expanding the phenotype of mutations in DICER1: mosaic missense mutations in the RNase IIIb domain of DICER1 cause GLOW syndrome.
J Med Genet. 2014; 51(5):294-302 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
BACKGROUND: Constitutional DICER1 mutations have been associated with pleuropulmonary blastoma, cystic nephroma, Sertoli-Leydig tumours and multinodular goitres, while somatic DICER1 mutations have been reported in additional tumour types. Here we report a novel syndrome termed GLOW, an acronym for its core phenotypic findings, which include Global developmental delay, Lung cysts, Overgrowth and Wilms tumour caused by mutations in the RNase IIIb domain of DICER1.
METHODS AND RESULTS: We performed whole exome sequencing on peripheral mononuclear blood cells of an affected proband and identified a de novo missense mutation in the RNase IIIb domain of DICER1. We confirmed an additional de novo missense mutation in the same domain of an unrelated case by Sanger sequencing. These missense mutations in the RNase IIIb domain of DICER1 are suspected to affect one of four metal binding sites located within this domain. Pyrosequencing was used to determine the relative abundance of mutant alleles in various tissue types. The relative mutation abundance is highest in Wilms tumour and unaffected kidney samples when compared with blood, confirming that the mutation is mosaic. Finally, we performed bioinformatic analysis of microRNAs expressed in murine cells carrying specific Dicer1 RNase IIIb domain metal binding site-associated mutations. We have identified a subset of 3p microRNAs that are overexpressed whose target genes are over-represented in mTOR, MAPK and TGF-β signalling pathways.
CONCLUSIONS: We propose that mutations affecting the metal binding sites of the DICER1 RNase IIIb domain alter the balance of 3p and 5p microRNAs leading to deregulation of these growth signalling pathways, causing a novel human overgrowth syndrome.

Busch M, Schwindt H, Brandt A, et al.
Classification of a frameshift/extended and a stop mutation in WT1 as gain-of-function mutations that activate cell cycle genes and promote Wilms tumour cell proliferation.
Hum Mol Genet. 2014; 23(15):3958-74 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
The WT1 gene encodes a zinc finger transcription factor important for normal kidney development. WT1 is a suppressor for Wilms tumour development and an oncogene for diverse malignant tumours. We recently established cell lines from primary Wilms tumours with different WT1 mutations. To investigate the function of mutant WT1 proteins, we performed WT1 knockdown experiments in cell lines with a frameshift/extension (p.V432fsX87 = Wilms3) and a stop mutation (p.P362X = Wilms2) of WT1, followed by genome-wide gene expression analysis. We also expressed wild-type and mutant WT1 proteins in human mesenchymal stem cells and established gene expression profiles. A detailed analysis of gene expression data enabled us to classify the WT1 mutations as gain-of-function mutations. The mutant WT1(Wilms2) and WT1(Wilms3) proteins acquired an ability to modulate the expression of a highly significant number of genes from the G2/M phase of the cell cycle, and WT1 knockdown experiments showed that they are required for Wilms tumour cell proliferation. p53 negatively regulates the activity of a large number of these genes that are also part of a core proliferation cluster in diverse human cancers. Our data strongly suggest that mutant WT1 proteins facilitate expression of these cell cycle genes by antagonizing transcriptional repression mediated by p53. We show that mutant WT1 can physically interact with p53. Together the findings show for the first time that mutant WT1 proteins have a gain-of-function and act as oncogenes for Wilms tumour development by regulating Wilms tumour cell proliferation.

Koller K, Pichler M, Koch K, et al.
Nephroblastomas show low expression of microR-204 and high expression of its target, the oncogenic transcription factor MEIS1.
Pediatr Dev Pathol. 2014 May-Jun; 17(3):169-75 [PubMed] Related Publications
By comparing several studies we identified a possible deregulation of the transcription factors PBX2 (pre-B-cell leukemia homeobox 2) and one of its binding partners, MEIS1 (Meis homeobox 1) in nephroblastomas. The regulation of MEIS1 is complex, and its expression is known to be influenced by changes of promoter methylation and binding of microRNA-204 (miR-204). Therefore, in our study, we assessed the expression of MEIS1 and PBX2 and the factors regulating expression of MEIS1 in nephroblastomas. MEIS1 and PBX2 messenger RNA (mRNA) and protein levels were investigated by quantitative real-time-polymerase chain reaction (qRT-PCR) and immunohistochemistry. Promoter methylation of MEIS1 was evaluated using a methylation-specific PCR assay. Expression levels of miR-204 were examined by qRT-PCR. Eighteen of 21 nephroblastomas showed a high level of MEIS1 mRNA, and 22 of 26 samples had a specific nuclear protein expression. MicroRNA-204 had a statistically significantly lower expression in all nephroblastomas investigated compared with renal parenchyma, but no change of MEIS1 promoter methylation status was noted. Eleven of 23 nephroblastomas had a high expression of PBX2 mRNA, and 15 of 23 samples had a specific nuclear protein expression was noted. In our study, we demonstrated an expression of MEIS1 and its binding partner PBX2 in most nephroblastomas. The statistically significantly lower expression of miR-204 in all nephroblastomas investigated might point to an involvement of miR-204 in the regulation of MEIS1 in nephroblastomas.

Starr LJ, Sanmann JN, Olney AH, et al.
Occurrence of nephroblastomatosis with dup(18)(q11.2-q23) implicates trisomy 18 tumor screening protocol in select patients with 18q duplication.
Am J Med Genet A. 2014; 164A(4):1079-82 [PubMed] Related Publications
Duplications of the long arm of chromosome 18 have been previously reported in patients with phenotypic findings similar to full trisomy 18. Trisomy 18 increases the risk for Wilms tumor and it is currently recommended that these patients undergo abdominal ultrasonography screening every 6 months. We report on nephroblastomatosis in a 27-month-old male with a 55 Mb duplication of chromosome 18q11.2-q23 (chr18:22693370-77982126, hg 19) and propose that the trisomy 18 tumor screening protocol could also benefit patients with large 18q duplications.

Zitzmann F, Mayr D, Berger M, et al.
Frequent hypermethylation of a CTCF binding site influences Wilms tumor 1 expression in Wilms tumors.
Oncol Rep. 2014; 31(4):1871-6 [PubMed] Related Publications
The Wilms tumor 1 (WT1) gene plays an essential role in early development and differentiation of the urinary tract, particularly the kidneys. Aberrant transcriptional activity of WT1 is a key finding in the genesis of Wilms tumors (WTs). However, the mechanisms responsible for this alteration remain poorly understood. In the present study, we examined the methylation pattern of a putative CCCTC-binding factor (CTCF) binding site downstream of the WT1 gene as a potential cause of WT1 misregulation in 44 native WT specimens. We found that 16 WT cases exhibited a much higher WT1 expression compared to normal kidney tissue, and that the high mRNA expression of WT1 is strongly correlated with a high degree of DNA methylation of the CTCF binding site near the WT1 promoter. However, there was no correlation between the KTS+/KTS- splicing variants of WT1 and the methylation status of the CpGs of the CTCF binding site. Our results demonstrated an aberrant methylation pattern at a CTCF binding site downstream the WT1 gene, which is associated with an elevated WT1 transcriptional activity. Thus, methylation of the CTCF binding site may be partially responsible for the transcriptional activation of the WT1 locus and hypermethylation of this site may be an important oncogenic mechanism in the genesis of WT.

Yi T, Weng J, Siwko S, et al.
LGR4/GPR48 inactivation leads to aniridia-genitourinary anomalies-mental retardation syndrome defects.
J Biol Chem. 2014; 289(13):8767-80 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
AGR syndrome (the clinical triad of aniridia, genitourinary anomalies, and mental retardation, a subgroup of WAGR syndrome for Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation) is a rare syndrome caused by a contiguous gene deletion in the 11p13-14 region. However, the mechanisms of WAGR syndrome pathogenesis are elusive. In this study we provide evidence that LGR4 (also named GPR48), the only G-protein-coupled receptor gene in the human chromosome 11p12-11p14.4 fragment, is the key gene responsible for the diseases of AGR syndrome. Deletion of Lgr4 in mouse led to aniridia, polycystic kidney disease, genitourinary anomalies, and mental retardation, similar to the pathological defects of AGR syndrome. Furthermore, Lgr4 inactivation significantly increased cell apoptosis and decreased the expression of multiple important genes involved in the development of WAGR syndrome related organs. Specifically, deletion of Lgr4 down-regulated the expression of histone demethylases Jmjd2a and Fbxl10 through cAMP-CREB signaling pathways both in mouse embryonic fibroblast cells and in urinary and reproductive system mouse tissues. Our data suggest that Lgr4, which regulates eye, kidney, testis, ovary, and uterine organ development as well as mental development through genetic and epigenetic surveillance, is a novel candidate gene for the pathogenesis of AGR syndrome.

Doros LA, Rossi CT, Yang J, et al.
DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.
Mod Pathol. 2014; 27(9):1267-80 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

Yamamoto T, Togawa M, Shimada S, et al.
Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.
Am J Med Genet A. 2014; 164A(3):634-8 [PubMed] Related Publications
Interstitial deletions of the 11p13 region are known to cause WAGR (Wilms tumor, aniridia, genitourinary malformation, and "mental retardation") syndrome, a contiguous gene deletion syndrome due to haploinsufficiencies of the genes in this region, including WT1 and PAX6. Developmental delay and autistic features are major complications of this syndrome. Previously, some genes located in this region have been suggested as responsible for autistic features. In this study, we identified two patients who showed the chromosomal deletions involving 11p13. Patient 1, having an 8.6 Mb deletion of chr11p14.1p12:29,676,434-38,237,948, exhibited a phenotype typical of WAGR syndrome and had severe developmental delay and autistic behaviors. On the other hand, Patient 2 had a larger aberration region in 11p14.1-p12 which was split into two regions, that is, a 2.2-Mb region of chr11p14.1: 29,195,161-31,349,732 and a 10.5-Mb region of chr11p13p12: 32,990,627-43,492,580. As a consequence, 1.6 Mb region of the WAGR syndrome critical region was intact between the two deletions. This patient showed no symptom of WAGR syndrome and no autistic behaviors. Therefore, the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down to the region remaining intact in Patient 2. Thus, the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome.

Karki S, Surolia R, Hock TD, et al.
Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis.
FASEB J. 2014; 28(3):1122-31 [PubMed] Article available free on PMC after 17/03/2016 Related Publications
Pleural mesothelial cells (PMCs), which are derived from the mesoderm, exhibit an extraordinary capacity to undergo phenotypic changes during development and disease. PMC transformation and trafficking has a newly defined role in idiopathic pulmonary fibrosis (IPF); however, the contribution of Wilms' tumor 1 (Wt1)-positive PMCs to the generation of pathognomonic myofibroblasts remains unclear. PMCs were obtained from IPF lung explants and healthy donor lungs that were not used for transplantation. Short hairpin Wt1-knockdown PMCs (sh Wt1) were generated with Wt1 shRNA, and morphologic and functional assays were performed in vitro. Loss of Wt1 abrogated the PMC phenotype and showed evidence of mesothelial-to-mesenchymal transition (MMT), with a reduced expression of E-cadherin and an increase in the profibrotic markers α-smooth muscle actin (α-SMA) and fibronectin, along with increased migration and contractility, compared with that of the control. Migration of PMCs in response to active transforming growth factor (TGF)-β1 was assessed by live-cell imaging with 2-photon microscopy and 3D imaging, of Wt1-EGFP transgenic mice. Lineage-tracing experiments to map the fate of Wt1(+) PMCs in mouse lung in response to TGF-β1 were also performed by using a Cre-loxP system. Our results, for the first time, demonstrate that Wt1 is necessary for the morphologic integrity of pleural membrane and that loss of Wt1 contributes to IPF via MMT of PMCs into a myofibroblast phenotype.

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

Ozdemir DD, Hohenstein P
Wt1 in the kidney--a tale in mouse models.
Pediatr Nephrol. 2014; 29(4):687-93 [PubMed] Related Publications
The WT1 gene was originally identified through its involvement in the development of Wilms tumours. The gene is characterized by a plethora of different isoforms with, in some cases, clearly different functions in transcriptional control and RNA metabolism. Many different mouse models for Wt1 have already been generated, and these are increasingly providing new information on the molecular roles of Wt1 in normal development and disease. In this review we discuss the different models that have been generated and what they have taught us about the role of Wt1 in the kidney.

An Q, Wang Y, An R, et al.
Association of E2F3 expression with clinicopathological features of Wilms' tumors.
J Pediatr Surg. 2013; 48(11):2187-93 [PubMed] Related Publications
PURPOSE: The transcription factor E2F3 plays an important role in controlling cell cycle progression and proliferation, and is overexpressed in various human cancers. The present study was undertaken to examine the expression of E2F3 and investigate its relevance in clinical and pathological features of pediatric Wilms' tumors.
METHODS: Twenty-six Wilms' tumor samples collected at the First Affiliated Hospital of Harbin Medical University underwent immunohistochemical staining for E2F3 protein expression by measuring the percentage of E2F3-positive cells and integrated optical density (IOD), and quantitative real-time polymerase chain reaction (qRT-PCR) for E2F3 mRNA expression.
RESULTS: The expression of E2F3 protein and mRNA was detectable in all the Wilms' tumor samples with big variations (The average percentage of positive cells was 30.2%±23.5%, range 0.3%-75.6%; average IOD was 6.61×10(4)±3.92×10(4), range 2.32×10(4)-13.84×10(4); average relative mRNA unit was 0.54±0.38, range 0.03-1.31), but not in fetal kidney tissues. Wilms' tumors with aggressive features, such as higher stage, unfavorable histology and higher risk level, expressed higher levels of E2F3 protein and mRNA.
CONCLUSIONS: The preliminary data indicate that E2F3 is frequently expressed in pediatric Wilms' tumors examined in the present study. E2F3 expression may be associated with Wilms' tumors, particularly those that have more aggressive features. However, further studies are needed to validate these pilot observations and to clarify the functional and mechanistic significance of this association.

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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