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
See also: Wilms' Tumour - clinical resources (11)
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex
Mutated Genes and Abnormal Protein Expression (78)
Clicking 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 || 525|
|IGF2 ||11p15.5 ||GRDF, IGF-II, PP9974, C11orf43 ||Imprinting errors ||-IGF2 Imprinting and Overexpression in Wilms' Tumour || 96|
|H19 ||11p15.5 ||ASM, BWS, WT2, ASM1, D11S813E, LINC00008, NCRNA00008 || ||-H19 and Wilms Tumour || 62|
|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, ASGD5, 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|
|MYCN ||2p24.3 ||NMYC, ODED, MODED, N-myc, bHLHe37 ||Amplification ||-MYCN amplification in Wilms Tumor || 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|
|CD99 ||Xp22.32 and Yp11.3 ||MIC2, HBA71, MIC2X, MIC2Y, MSK5X || ||-CD99 and Wilms Tumour || 7|
|IGF2R ||6q26 ||MPR1, MPRI, CD222, CIMPR, M6P-R ||Germline |
|-IGF2R Imprinting Errors in Wilms' Tumour || 7|
|DIS3L2 ||2q37.1 ||FAM6A, PRLMNS, hDIS3L2 || ||-DIS3L2 and Wilms Tumour || 7|
|KCNQ1 ||11p15.5-p15.4 ||LQT, RWS, WRS, LQT1, SQT2, ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, Kv1.9, Kv7.1, KVLQT1 || ||-KCNQ1 and Wilms Tumour || 7|
|KCNQ1OT1 ||11p15.5 ||LIT1, Kncq1, KvDMR1, KCNQ10T1, KCNQ1-AS2, KvLQT1-AS, NCRNA00012 || ||-KCNQ1OT1 and Wilms Tumour || 6|
|DICER1 ||14q32.13 ||DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE || ||-DICER1 and Wilms Tumour || 6|
|CITED1 ||Xq13.1 ||MSG1 || ||-CITED1 and Wilms Tumour || 6|
|BIRC5 ||17q25 ||API4, EPR-1 || ||-BIRC5 and Wilms Tumour || 5|
|CDKN2A ||9p21.3 ||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 || 5|
|HACE1 ||6q16.3 || || ||-HACE1 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|
|SIX1 ||14q23.1 ||BOS3, TIP39, DFNA23 || ||-SIX1 and Wilms Tumour || 3|
|STIM1 ||11p15.4 ||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|
|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|
|FBXW7 ||4q31.3 ||AGO, CDC4, FBW6, FBW7, hAgo, FBX30, FBXW6, SEL10, hCdc4, FBXO30, SEL-10 || ||-FBXW7 mutations in Wilms Tumor || 2|
|IGF2-AS ||11p15.5 ||PEG8, IGF2AS, IGF2-AS1 || ||-IGF2-AS and Wilms Tumour || 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, PCT, CGRP, CALC1, CGRP1, CGRP-I || ||-CALCA and Wilms Tumour || 2|
|PPP2CA ||5q31.1 ||RP-C, PP2Ac, PP2CA, PP2Calpha || ||-PPP2CA and Wilms Tumour || 2|
|DGCR8 ||22q11.2 ||Gy1, pasha, DGCRK6, C22orf12 || ||-DGCR8 and Wilms Tumour || 2|
|MEST ||7q32 ||PEG1 || ||-MEST and Wilms Tumour || 2|
|SMARCA4 ||19p13.2 ||BRG1, CSS4, SNF2, SWI2, MRD16, RTPS2, BAF190, SNF2L4, SNF2LB, hSNF2b, BAF190A || ||-SMARCA4 and Wilms Tumour || 2|
|SLC22A18 ||11p15.4 ||HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A || ||-SLC22A18 and Wilms Tumour || 2|
|RRM1 ||11p15.4 ||R1, RR1, RIR1 || ||-RRM1 and Wilms Tumour || 2|
|RARRES3 ||11q12.3 ||RIG1, TIG3, HRSL4, HRASLS4, PLA1/2-3 || ||-RARRES3 and Wilms Tumour || 2|
|HOXB4 ||17q21.32 ||HOX2, HOX2F, HOX-2.6 || ||-HOXB4 and Wilms Tumour || 1|
|MOS ||8q11 ||MSV || ||-MOS 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|
|HOXD10 ||2q31.1 ||HOX4, HOX4D, HOX4E, Hox-4.4 || ||-HOXD10 and Wilms Tumour || 1|
|CACNA1E ||1q25.3 ||BII, CACH6, Cav2.3, CACNL1A6 ||Prognostic ||-CACNA1E overexpression in Wilms Tumor || 1|
|ARHGEF1 ||19q13.13 ||LSC, GEF1, LBCL2, SUB1.5, P115-RHOGEF || ||-ARHGEF1 and Wilms Tumour || 1|
|KRT18 ||12q13 ||K18, CK-18, CYK18 || ||-KRT18 and Wilms Tumour || 1|
|KRT8 ||12q13 ||K8, KO, CK8, CK-8, CYK8, K2C8, CARD2 || ||-KRT8 and Wilms Tumour || 1|
|SELL ||1q24.2 ||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|
|PEG10 ||7q21 ||EDR, HB-1, Mar2, MEF3L, Mart2, RGAG3 || ||-PEG10 and Wilms Tumour || 1|
|RAB25 ||1q22 ||CATX-8, RAB11C || ||-RAB25 and Wilms Tumour || 1|
|MYH11 ||16p13.11 ||AAT4, FAA4, SMHC, SMMHC || ||-MYH11 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|
|LIN28B ||6q21 ||CSDD2 || ||-LIN28B and Wilms Tumour || 1|
|PPP2R1A ||19q13.41 ||MRD36, PR65A, PP2AAALPHA, PP2A-Aalpha || ||-PPP2R1A and Wilms Tumour || 1|
|PPP2R1B ||11q23.1 ||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|
|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|
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
Micale MA, Embrey B, Macknis JK, et al.Constitutional 560.49 kb chromosome 2p24.3 duplication including the MYCN gene identified by SNP chromosome microarray analysis in a child with multiple congenital anomalies and bilateral Wilms tumor.
Eur J Med Genet. 2016; 59(12):618-623 [PubMed
] Related Publications
Fewer than 100 patients with partial chromosome 2p trisomy have been reported. Clinical features are variable and depend on the size of the duplicated segment, but generally include psychomotor delay, facial anomalies, congenital heart defect, and other abnormalities. We report a 560.49 kb duplication of chromosome 2p in a 13 month-old male with hydrocephaly, ventricular septal defect, partial agenesis of the corpus callosum, and bilateral Wilms tumor. After discovery of bilateral renal masses at four months of age, the child underwent neoadjuvant chemotherapy followed by right radical nephrectomy that revealed triphasic Wilms' tumor. A needle core biopsy on one of two lesions on the left kidney also revealed Wilms tumor. A partial left nephrectomy revealed focally positive margins that necessitated left flank radiotherapy. The tumor karyotype was 46,XY,t(7;8)(q36;p11)/46,XY  while his constitutional karyotype was 46,XY, suggesting that the t(7;8)(q36;p11) was associated with the malignancy. Single nucleotide polymorphism (SNP) chromosome microarray analysis of peripheral blood identified a maternally-inherited 560.49 kb chromosome 2p24.3 duplication that involved four OMIM genes: NBAS, DDX1, MYCNOS, and MYCN. SNP array analysis of the tumor revealed the same 2p24.3 duplication. At present, the now 5-year-old boy continues to do well without clinical or radiographic evidence of recurrent disease. This case is instructive because the child's health insurer initially denied authorization for chromosome microarray analysis (CMA), and it took more than one year before such authorization was finally granted. That initial decision to deny coverage could have had untoward health implications for this child, as the identification of constitutional MYCN duplication necessitated surveillance imaging for a number of pediatric malignancies associated with MYCN overexpression/dysregulation.
Teng WJ, Zhou C, Liu LJ, et al.Construction of a protein-protein interaction network of Wilms' tumor and pathway prediction of molecular complexes.
Genet Mol Res. 2016; 15(2) [PubMed
] Related Publications
Wilms' tumor (WT), or nephroblastoma, is the most common malignant renal cancer that affects the pediatric population. Great progress has been achieved in the treatment of WT, but it cannot be cured at present. Nonetheless, a protein-protein interaction network of WT should provide some new ideas and methods. The purpose of this study was to analyze the protein-protein interaction network of WT. We screened the confirmed disease-related genes using the Online Mendelian Inheritance in Man database, created a protein-protein interaction network based on biological function in the Cytoscape software, and detected molecular complexes and relevant pathways that may be included in the network. The results showed that the protein-protein interaction network of WT contains 654 nodes, 1544 edges, and 5 molecular complexes. Among them, complex 1 is predicted to be related to the Jak-STAT signaling pathway, regulation of hematopoiesis by cytokines, cytokine-cytokine receptor interaction, cytokine and inflammatory responses, and hematopoietic cell lineage pathways. Molecular complex 4 shows a correlation of WT with colorectal cancer and the ErbB signaling pathway. The proposed method can provide the bioinformatic foundation for further elucidation of the mechanisms of WT development.
Huang L, Mokkapati S, Hu Q, et al.Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with β-Catenin Activation or Wt1 Ablation and Igf2 Upregulation.
Neoplasia. 2016; 18(2):71-81 [PubMed
] Free Access to Full Article Related Publications
Wilms tumor, a common childhood tumor of the kidney, is thought to arise from undifferentiated renal mesenchyme. Variable tumor histology and the identification of tumor subsets displaying different gene expression profiles suggest that tumors may arise at different stages of mesenchyme differentiation and that this ontogenic variability impacts tumor pathology, biology, and clinical outcome. To test the tumorigenic potential of different cell types in the developing kidney, we used kidney progenitor-specific Cre recombinase alleles to introduce Wt1 and Ctnnb1 mutations, two alterations observed in Wilms tumor, into embryonic mouse kidney, with and without biallelic Igf2 expression, another alteration that is observed in a majority of tumors. Use of a Cre allele that targets nephron progenitors to introduce a Ctnnb1 mutation that stabilizes β-catenin resulted in the development of tumors with a predominant epithelial histology and a gene expression profile in which genes characteristic of early renal mesenchyme were not expressed. Nephron progenitors with Wt1 ablation and Igf2 biallelic expression were also tumorigenic but displayed a more triphasic histology and expressed early metanephric mesenchyme genes. In contrast, the targeting of these genetic alterations to stromal progenitors did not result in tumors. These data demonstrate that committed nephron progenitors can give rise to Wilms tumors and that committed stromal progenitors are less tumorigenic, suggesting that human Wilms tumors that display a predominantly stromal histology arise from mesenchyme before commitment to a stromal lineage.
Over the last few decades, numerous biomarkers in Wilms' tumor have been confirmed and shown variations in prevalence. Most of these studies were based on small sample sizes. We carried out a meta-analysis of the research published from 1992 to 2015 to obtain more precise and comprehensive outcomes for genetic tests. In the present study, 70 out of 5175 published reports were eligible for the meta-analysis, which was carried out using Stata 12.0 software. Pooled prevalence for gene mutations WT1, WTX, CTNNB1, TP53, MYCN, DROSHA, and DGCR8 was 0.141 (0.104, 0.178), 0.147 (0.110, 0.184), 0.140 (0.100, 0.190), 0.410 (0.214, 0.605), 0.071 (0.041, 0.100), 0.082 (0.048, 0.116), and 0.036 (0.026, 0.046), respectively. Pooled prevalence of loss of heterozygosity at 1p, 11p, 11q, 16q, and 22q was 0.109 (0.084, 0.133), 0.334 (0.295, 0.373), 0.199 (0.146, 0.252), 0.151 (0.129, 0.172), and 0.148 (0.108, 0.189), respectively. Pooled prevalence of 1q and chromosome 12 gain was 0.218 (0.161, 0.275) and 0.273 (0.195, 0.350), respectively. The limited prevalence of currently known genetic alterations in Wilms' tumors indicates that significant drivers of initiation and progression remain to be discovered. Subgroup analyses indicated that ethnicity may be one of the sources of heterogeneity. However, in meta-regression analyses, no study-level characteristics of indicators were found to be significant. In addition, the findings of our sensitivity analysis and possible publication bias remind us to interpret results with caution.
Hillen LM, Kamsteeg EJ, Schoots J, et al.Refining the Diagnosis of Congenital Nephrotic Syndrome on Long-term Stored Tissue: c.1097G>A (p.(Arg366His)) WT1 Mutation Causing Denys Drash Syndrome.
Fetal Pediatr Pathol. 2016; 35(2):112-9 [PubMed
] Related Publications
Congenital nephrotic syndrome (CNS) caused by a mutation in the Wilms tumor 1 suppressor gene (WT1) is part of Denys Drash Syndrome or Frasier syndrome. In the framework of genetic counseling, the diagnosis of CNS can be refined with gene mutation studies on long-term stored formalin-fixed paraffin-embedded tissue from postmortem examination. We report a case of diffuse mesangial sclerosis with perinatal death caused by a de novo mutation in the WT1 gene in a girl with an XY-genotype. This is the first case of Denys Drash Syndrome with the uncommon missense c.1097G>A [p.(Arg366His)] mutation in the WT1 gene which has been diagnosed on long-term stored formalin-fixed paraffin-embedded tissue in 1993. This emphasizes the importance of retained and adequately stored tissue as a resource in the ongoing medical care and counseling.
Approximately half of children suffering from recurrent Wilms tumor (WT) develop resistance to salvage therapies. Hence the importance to disclose events driving tumor progression/recurrence. Future therapeutic trials, conducted in the setting of relapsing patients, will need to prioritize targets present in the recurrent lesions. Different studies identified primary tumor-specific signatures associated with poor prognosis. However, given the difficulty in recruiting specimens from recurrent WTs, little work has been done to compare the molecular profile of paired primary/recurrent diseases. We studied the genomic profile of a cohort of eight pairs of primary/recurrent WTs through whole-genome SNP arrays, and investigated known WT-associated genes, including SIX1, SIX2 and micro RNA processor genes, whose mutations have been recently proposed as associated with worse outcome. Through this approach, we sought to uncover anomalies characterizing tumor recurrence, either acquired de novo or already present in the primary disease, and to investigate whether they overlapped with known molecular prognostic signatures. Among the aberrations that we disclosed as potentially acquired de novo in recurrences, some had been already recognized in primary tumors as associated with a higher risk of relapse. These included allelic imbalances of chromosome 1q and of chromosome 3, and CN losses on chromosome 16q. In addition, we found that SIX1 and DROSHA mutations can be heterogeneous events (both spatially and temporally) within primary tumors, and that their co-occurrence might be positively selected in the progression to recurrent disease. Overall, these results provide new insights into genomic and genetic events underlying WT progression/recurrence.
Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests. These data support a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumour.
Wilms' tumor is the most common renal tumor in children in which diffusely anaplastic or unfavorable histology foreshadows poor prognosis. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. Accumulating evidence shows that microRNA dysregulation takes part in the pathogenesis of many renal diseases, such as chronic kidney diseases, polycystic kidney disease, renal fibrosis, and renal cancers. In Wilms' tumor, dysregulation of some key oncogenic or tumor-suppressing microRNAs, such as miR-17~92 cluster, miR-185, miR-204, and miR-483, has been documented. In this review, we will summarize current evidence on the role of dysregulated microRNAs in the development of Wilms' tumor.
BACKGROUND: DNA hypomethylation of long interspersed nuclear elements-1 (LINEs-1) occurs during carcinogenesis, whereas information addressing LINE-1 methylation in Wilms tumor (WT) is limited. The main purpose of our study was to quantify LINE-1 methylation levels and evaluate their relationship with relative telomere length (TL) in WT.
METHODS: We investigated LINE-1 methylation and relative TL using bisulfite-polymerase chain reaction (PCR) pyrosequencing and quantitative PCR, respectively, in 20 WT tissues, 10 normal kidney tissues and a WT cell line. Significant changes were analyzed by t-tests.
RESULTS: LINE-1 methylation levels were significantly lower (P < 0.05) and relative TLs were significantly shorter (P < 0.05) in WT compared with normal kidney. There was a significant positive relationship between LINE-1 methylation and relative TL in WT (r = 0.671, P = 0.001). LINE-1 Methylation levels were significantly associated with global DNA methylation (r = 0.332, P < 0.01). In addition, relative TL was shortened and LINE-1 methylation was decreased in a WT cell line treated with the hypomethylating agent 5-aza-2'-deoxycytidine compared with untreated WT cell line.
CONCLUSION: These results suggest that LINE-1 hypomethylation is common and may be linked to telomere shortening in WT.
Mahamdallie SS, Hanks S, Karlin KL, et al.Mutations in the transcriptional repressor REST predispose to Wilms tumor.
Nat Genet. 2015; 47(12):1471-4 [PubMed
] Related Publications
Wilms tumor is the most common childhood renal cancer. To identify mutations that predispose to Wilms tumor, we are conducting exome sequencing studies. Here we describe 11 different inactivating mutations in the REST gene (encoding RE1-silencing transcription factor) in four familial Wilms tumor pedigrees and nine non-familial cases. Notably, no similar mutations were identified in the ICR1000 control series (13/558 versus 0/993; P < 0.0001) or in the ExAC series (13/558 versus 0/61,312; P < 0.0001). We identified a second mutational event in two tumors, suggesting that REST may act as a tumor-suppressor gene in Wilms tumor pathogenesis. REST is a zinc-finger transcription factor that functions in cellular differentiation and embryonic development. Notably, ten of 11 mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. These data establish REST as a Wilms tumor predisposition gene accounting for ∼2% of Wilms tumor.
Fawzy M, Bahanassy A, Samir A, Hafez HProfiling Loss of Heterozygosity Patterns in a Cohort of Favorable Histology Nephroblastoma Egyptian Patients: What is Consistent With the Rest of the World.
Pediatr Hematol Oncol. 2015; 32(8):548-56 [PubMed
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According to the Fifth National Wilms Tumor Study (NWTS-5), tumor-specific loss of heterozygosity (LOH) for chromosomes 1p and 16q identifies a subset of patients with Wilms tumor (WT) who despite having favorable histology (FH) have a significantly increased risk of relapse and death. We aimed to find out 1p and 16q LOH frequencies in patients with FH-WT as well as its correlation to survival outcome and epidemiologic and clinical characteristics. Data of patients with FH-WT presenting to the National Cancer Institute, Egypt, were retrospectively analyzed. Paraffin blocks were tested for 1p and 16q LOH using polymorphic loci that span the minimal regions of LOH at this area. The study included 100 patients with a median age of 5 years. Thirty-nine patients (39%) showed LOH at 1p (n = 14), 16q (n = 13), or both (n = 12). LOH was most frequently encountered in patients above 10 years (5/5), advanced stages disease (80% of stage V and 50% of stages IV and III each). The 3-year overall survival (OS) and event-free survival (EFS) were significantly lower in patients with double LOH (75% and 50%, respectively), followed by 16q (92% and 54%), in comparison with 1p (93% each) and negative LOH (97% and 100%) cases, respectively (p = 0.001). Combined LOH (1p+16q), followed by 16q LOH alone, was predictive of poorer outcome and was associated with lower OS and EFS in patients with FH-WT. Our results showed a higher-risk disease that would suggest the need for an intensified upfront therapy in this group of patients.
Wilms tumor (WT), the most common cancer of the kidney in infants and children, has a complex etiology that is still poorly understood. Identification of genomic copy number variants (CNV) in tumor genomes provides a better understanding of cancer development which may be useful for diagnosis and therapeutic targets. In paired blood and tumor DNA samples from 14 patients with sporadic WT, analyzed by aCGH, 22% of chromosome abnormalities were novel. All constitutional alterations identified in blood were segmental (in 28.6% of patients) and were also present in the paired tumor samples. Two segmental gains (2p21 and 20q13.3) and one loss (19q13.31) present in blood had not been previously described in WT. We also describe, for the first time, a small, constitutive partial gain of 3p22.1 comprising 2 exons of CTNNB1, a gene associated to WT. Among somatic alterations, novel structural chromosomal abnormalities were found, like gain of 19p13.3 and 20p12.3, and losses of 2p16.1-p15, 4q32.5-q35.1, 4q35.2-q28.1 and 19p13.3. Candidate genes included in these regions might be constitutively (SIX3, SALL4) or somatically (NEK1, PIAS4, BMP2) operational in the development and progression of WT. To our knowledge this is the first report of CNV in paired blood and tumor samples in sporadic WT.
Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub-Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub-Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment-resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT-associated genes and evaluated whole-genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow-up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment-resistant.
Charlton J, Pavasovic V, Pritchard-Jones KBiomarkers to detect Wilms tumors in pediatric patients: where are we now?
Future Oncol. 2015; 11(15):2221-34 [PubMed
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Wilms tumor (WT) is the most common pediatric renal tumor. Survival rates are high, whether treated according to the European protocols (SIOP-RTSG) that use prenephrectomy chemotherapy or the Children's Oncology Group (COG) protocols, with immediate nephrectomy. However, the more intensive treatment given to higher risk subgroups may result in late effects. Current risk stratification does not identify all tumors that relapse and loss of heterozygosity of 16q and 1p are the only molecular biomarkers used in risk stratification. In this review we describe recent new genetic and epigenetic findings in WT and discuss their potential use as biomarkers. We discuss approaches to ensure representative sampling of WTs including the potential for 'liquid biopsy' to circumvent intratumoral heterogeneity.
Song D, Yue L, Wu G, et al.Evaluation of promoter hypomethylation and expression of p73 as a diagnostic and prognostic biomarker in Wilms' tumour.
J Clin Pathol. 2016; 69(1):12-8 [PubMed
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AIMS: A member of the p53 family, the p73 gene is essential for the maintenance of genomic stability, DNA repair and apoptosis regulation. This study was designed to evaluate the utility of expression and DNA methylation patterns of the p73 gene in the early diagnosis and prognosis of Wilms' tumour (WT).
METHODS: Methylation-specific PCR, semi-quantitative (sq-PCR), real-time quantitative PCR (qRT-PCR), receiver operating characteristic (ROC), and survival and hazard function curve analyses were utilised to measure the expression and DNA methylation patterns of p73 in WT tissue samples with a view to assessing diagnostic and prognostic value.
RESULTS: The relative expression of p73 mRNA was higher, while the promoter methylation level was lower in the WT than the control group (p<0.05) and closely associated with poor survival prognosis in children with WT (p<0.05). Increased expression and decreased methylation of p73 were correlated with increasing tumour size, clinical stage and unfavourable histological differentiation (p<0.05). ROC curve analysis showed areas under the curve of 0.544 for methylation and 0.939 for expression in WT venous blood, indicating the higher diagnostic yield of preoperative p73 expression.
CONCLUSIONS: Preoperative venous blood p73 level serves as an underlying biomarker for the early diagnosis of WT. p73 overexpression and concomitantly decreased promoter methylation are significantly associated with poor survival in children with WT.
BACKGROUND: Wilms' tumor (WT) is the most common malignant renal tumor in children. Previous studies suggested the reversion-inducing, cysteine-rich protein with Kazal motifs (RECK) down-regulation might have a role in numerous human cancers. The current study was done to investigate the associations of RECK single-nucleotide polymorphisms (SNPs) with the WT susceptibility in Chinese children.
MATERIAL AND METHODS: We analyzed 2 SNPs (rs10972727 and rs11788747) in a total of 97 WT children and 194 healthy matched controls (1:2 ratio) by real-time PCR and PCR-RFLP genotyping analysis.
RESULTS: We found that the G allele of rs11788747 in the RECK gene was significantly associated with WT in Chinese children (OR=0.7, 95% CI: 0.45-0.99; P=0.042); as with another SNP rs10972727, however, no statistically significant difference was detected. Further analysis showed there was also a statistically significant difference in genotype frequencies between terminal tumor stage (P=0.026) and metastatic groups (P=0.002).
CONCLUSIONS: The present data indicate that there is a significant association between mutant G of rs11788747 in RECK and WT risk. G carriers with advanced tumor stage or with metastasis might have an increased risk of WT.
Yoshizawa S, Fujiwara K, Sugito K, et al.Pyrrole-imidazole polyamide-mediated silencing of KCNQ1OT1 expression induces cell death in Wilms' tumor cells.
Int J Oncol. 2015; 47(1):115-21 [PubMed
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KvDMR (an intronic CpG island within the KCNQ1 gene) is one of the imprinting control regions on human chromosome 11p15.5. Since KvDMR exists within the promoter region of KCNQ1OT1 (antisense transcript of KCNQ1), it is likely that genomic alterations of this region including deletion, paternal uniparental disomy and de-methylation in maternal allele lead to aberrant overexpression of KCNQ1OT1. Indeed, de-methylation of KvDMR accompanied by uncontrolled overexpression of KCNQ1OT1 occurs frequently in Beckwith-Wiedemann syndrome (BWS), and around 10% of BWS patients developed embryonal tumors (Wilms' tumor or hepatoblastoma). These observations strongly suggest that silencing of KCNQ1OT1 expression might suppress its oncogenic potential. In the present study, we designed two pyrrole-imidazole (PI) polyamides, termed PI-a and PI-b, which might have the ability to bind to CCAAT boxes of the KCNQ1OT1 promoter region, and investigated their possible antitumor effect on Wilms' tumor-derived G401 cells. Gel retardation assay demonstrated that PI-a and PI-b specifically bind to their target sequences. Microscopic observations showed the efficient nuclear access of these PI polyamides. Quantitative real-time PCR analysis revealed that the expression level of KCNQ1OT1 was significantly decreased when treated with PI-a and PI-b simultaneously but not with either PI-a or PI-b single treatment. Consistent with these results, the combination of PI-a and PI-b resulted in a significant reduction in viability of G401 cells in a dose-dependent manner. Furthermore, FACS analysis demonstrated that combinatory treatment with PI-a and PI-b induces cell death as compared with control cells. Taken together, our present observations strongly suggest that the combinatory treatment with PI polyamides targeting KCNQ1OT1 might be a novel therapeutic strategy to cure patients with tumors over-expressing KCNQ1OT1.
PURPOSE: Wilms tumor is the most common renal neoplasm of childhood. We previously found that restricted activation of the WNT/β-catenin pathway in renal epithelium late in kidney development is sufficient to induce small primitive neoplasms with features of epithelial Wilms tumor. Metastatic disease progression required simultaneous addition of an activating mutation of the oncogene K-RAS. We sought to define the molecular pathways activated in this process and their relationship to human renal malignancies.
MATERIALS AND METHODS: Affymetrix® expression microarray data from murine kidneys with activation of K-ras and/or Ctnnb1 (β-catenin) restricted to renal epithelium were analyzed and compared to publicly available expression data on normal and neoplastic human renal tissue. Target genes were verified by immunoblot and immunohistochemistry.
RESULTS: Mouse kidney tumors with activation of K-ras and Ctnnb1, and human renal malignancies had similar mRNA expression signatures and were associated with activation of networks centered on β-catenin and TP53. Up-regulation of WNT/β-catenin targets (MYC, Survivin, FOXA2, Axin2 and Cyclin D1) was confirmed by immunoblot. K-RAS/β-catenin murine kidney tumors were more similar to human Wilms tumor than to other renal malignancies and demonstrated activation of a TP53 dependent network of genes, including the transcription factor E2F1. Up-regulation of E2F1 was confirmed in murine and human Wilms tumor samples.
CONCLUSIONS: Simultaneous activation of K-RAS and β-catenin in embryonic renal epithelium leads to neoplasms similar to human Wilms tumor and associated with activation of TP53 and up-regulation of E2F1. Further studies are warranted to evaluate the role of TP53 and E2F1 in human Wilms tumor.
Song D, Yue L, Wu G, et al.Assessment of promoter methylation and expression of SIX2 as a diagnostic and prognostic biomarker in Wilms' tumor.
Tumour Biol. 2015; 36(10):7591-8 [PubMed
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This study was designed to evaluate the utility of expression and DNA methylation patterns of the sine oculis homeobox homolog 2 (SIX2) gene in early diagnosis and prognosis of Wilms' tumor (WT). Methylation-specific polymerase chain reaction (MSP), real-time quantitative polymerase chain reaction (qRT-PCR), receiver operating characteristic (ROC), and survival curve analyses were utilized to measure the expression and DNA methylation patterns of SIX2 in a cohort of WT tissues, with a view to assessing their diagnostic and prognostic value. Relative expression of SIX2 mRNA was higher, while the promoter methylation level was lower in the WT than control group (P < 0.05) and closely associated with poor survival prognosis of WT children (P < 0.05). Increased expression and decreased methylation of SIX2 were correlated with increasing tumor size, clinical stage, vascular invasion, and unfavorable histological differentiation (P < 0.05). ROC curve analysis showed areas under the curve (AUCs) of 0.579 for methylation and 0.917 for expression in WT venous blood, indicating higher diagnostic yield of preoperative SIX2 expression. The preoperative venous blood SIX2 expression level serves as an underlying biomarker for early diagnosis of WT. SIX2 overexpression and concomitantly decreased promoter methylation are significantly associated with poor survival of WT children.
Russell B, Johnston JJ, Biesecker LG, et al.Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance.
Am J Med Genet A. 2015; 167A(9):2122-31 [PubMed
] Free Access to Full Article Related Publications
Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture (flexion at the elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints), severe intellectual disability, and feeding issues. Nine patients with Bohring-Opitz syndrome have been identified as having a mutation in ASXL1. We report on eight previously unpublished patients with Bohring-Opitz syndrome caused by an apparent or confirmed de novo mutation in ASXL1. Of note, two patients developed bilateral Wilms tumors. Somatic mutations in ASXL1 are associated with myeloid malignancies, and these reports emphasize the need for Wilms tumor screening in patients with ASXL1 mutations. We discuss clinical management with a focus on their feeding issues, cyclic vomiting, respiratory infections, insomnia, and tumor predisposition. Many patients are noted to have distinctive personalities (interactive, happy, and curious) and rapid hair growth; features not previously reported.
Singh N, Sahu DK, Goel M, et al.Retrospective analysis of FFPE based Wilms' Tumor samples through copy number and somatic mutation related Molecular Inversion Probe Based Array.
Gene. 2015; 565(2):295-308 [PubMed
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In this report, retrospectively, we analyzed fifteen histo-pathologically characterized FFPE based Wilms' Tumor (WT) samples following an integrative approach of copy number (CN) and loss of heterozygosity (LOH) imbalances. The isolated-DNA was tested on CN and somatic-mutation related Molecular-Inversion-Probe based-Oncoscan Array™ and was analyzed through Nexus-Express OncoScan-3.0 and 7.0 software. We identified gain of 3p13.0-q29, 4p16.3-14.0, 7, 12p13.33-q24.33, and losses of 1p36.11-q44, 11p15.5-q25, 21q 22.2-22.3 and 22q11.21-13.2 in six samples (W1-6) and validated them in nine more samples (W7-9, W12-15, W17-18). Some observed that discrete deletions (1p, 1q, 10p, 10q, 13q, 20p) were specific to our samples. Maximum-LOH was observed in Ch11 as reported in previous studies. However, LOH was also observed in different regions of Ch7 including some cancer genes. The identified LOH-regions (1q21.2-q21.3, 2p24.1-23.3, 2p24.3-24.3, 3p21.3-21.1, 4p16.3, 7p11.2-p11.1, 7q31.2-31.32, 7q34-q35 and Ch 8) in W1-W6 were also validated in W7-9, W12-15 and W18. In addition, previously reported LOH of 1p and 16q region was also observed in our cases. The proven and novel onco (OG)- and tumor-suppressor genes (TSGs) involved in the CNV regions affected the major pathways like Chromatin Modification, RAS, PI3K; RAS in 14/15 cases, NOTCH/TGF-β and Cell Cycle Apoptosis in 10/15 cases, APC in 9/15 cases and Transcriptional Regulation in 7/15 cases, PI3K and genome maintenance in 6/15 cases. This exhaustive profiling of OG and TG may help in prognosis and diagnosis of the disease after validation of all the relevant results, especially the novel ones, obtained in this research in a larger number of samples.
Schlegelberger B, Kreipe H, Lehmann U, et al.A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies.
Pediatr Blood Cancer. 2015; 62(8):1481-4 [PubMed
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Here we report on a child with Li-Fraumeni syndrome with a de novo TP53 mutation c.818G>A, who developed three malignancies at the age of 4 months, 4 and 5 years, respectively. We show that (i) in the choroid plexus carcinoma, the germline mutation was detected in a homozygous state due to copy-neutral LOH/uniparental disomy, (ii) in the secondary AML, a complex karyotype led to loss of the wild-type TP53 allele, (iii) in the Wilms tumor, the somatic mutation c.814G>A led to compound heterozygosity. The findings show that the complete inactivation of TP53 by different mechanisms is an important step towards tumorigenesis.
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.
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
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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.
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.
Finken MJ, Hendriks YM, van der Voorn JP, et al.WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.
Horm Res Paediatr. 2015; 83(3):211-6 [PubMed
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BACKGROUND: Heterozygous missense mutations in the WT1 gene that affect the function of the wild-type allele have been identified in Denys-Drash syndrome, which is characterized by severe gonadal dysgenesis, early-onset nephropathy and a predisposition to renal and gonadal cancer. Intron 9 splice-site mutations that influence the balance between WT1 isoforms cause a nearly similar phenotype, known as Frasier syndrome. Nonsense mutations and deletions only lead to WT1 haploinsufficiency and, hence, to less severe gonadal dysgenesis and late-onset nephropathy. WT1 analysis is mandatory in 46,XY gonadal dysgenesis with renal abnormality.
PATIENT: We describe a newborn with 46,XY severe partial gonadal dysgenesis, in whom structural renal anomalies and proteinuria were excluded. Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive for a gonadoblastoma. At the age of 9 months, the patient presented with a bilateral Wilms tumor.
RESULTS: We found a heterozygous WT1 whole-gene deletion but no other gene defects.
CONCLUSIONS: This case description illustrates that a WT1 deletion might be associated with a more severe phenotype than previously thought. It also illustrates that, even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in 46,XY gonadal dysgenesis.
Montalvão-de-Azevedo R, Vasconcelos GM, Vargas FR, et al.RFC-1 80G>A polymorphism in case-mother/control-mother dyads is associated with risk of nephroblastoma and neuroblastoma.
Genet Test Mol Biomarkers. 2015; 19(2):75-81 [PubMed
] Free Access to Full Article Related Publications
AIM: Embryonic tumors are associated with an interruption during normal organ development; they may be related to disturbances in the folate pathway involved in DNA synthesis, methylation, and repair. Prenatal supplementation with folic acid is associated with a decreased risk of neuroblastoma, brain tumors, retinoblastoma, and nephroblastoma. The aim of this study was to investigate the association between MTHFR rs1801133 (C677T) and RFC-1 rs1051266 (G80A) genotypes with the risk of developing nephroblastoma and neuroblastoma.
MATERIALS AND METHODS: Case-mother/control-mother dyad study. Samples from Brazilian children with nephroblastoma (n=80), neuroblastoma (n=66), healthy controls (n=453), and their mothers (case n=93; control n=75) were analyzed. Genomic DNA was isolated from peripheral blood cells and/or buccal cells and genotyped to identify MTHFR C677T and RFC-1 G80A polymorphisms. Differences in genotype distribution between patients and controls were tested by multiple logistic regression analysis.
RESULTS: Risk for nephroblastoma and neuroblastoma was two- to fourfold increased among children with RFC-1 polymorphisms. An increased four- to eightfold risk for neuroblastoma and nephroblastoma was seen when the child and maternal genotypes were combined.
CONCLUSION: Our results suggest that mother and child RFC-1 G80A genotypes play a role on the risk of neuroblastoma and nephroblastoma since this polymorphism may impair the intracellular levels of folate, through carrying fewer folate molecules to the cell interior, and thus, the intracellular concentration is not enough to maintain regular DNA synthesis and methylation pathways.
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
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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
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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.
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
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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.
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 JBEpidemiological features of Wilms' tumor: results of the National Wilms' Tumor Study.
J Natl Cancer Inst. 1982; 68(3):429-36 [PubMed
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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
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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
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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
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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 MA16q loss of heterozygosity and microsatellite instability in Wilms' tumor.
J Pediatr Surg. 2000; 35(6):891-6; discussion 896-7 [PubMed
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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
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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.
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
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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.