Wilms tumor (WT) is one of the most common solid tumors of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. It is believed to result from malignant transformation of abnormally persistent renal ... Wilms tumor (WT) is one of the most common solid tumors of childhood, occurring in 1 in 10,000 children and accounting for 8% of childhood cancers. It is believed to result from malignant transformation of abnormally persistent renal stem cells which retain embryonic differentiation potential (Breslow and Beckwith, 1982; Rahman et al., 1996). The risk of Wilms tumor is increased in association with several recognizable congenital malformation syndromes, although these cases account for less than 5% of all clinical patients with Wilms tumor (Tsuchida et al., 1995). The 'WAGR' syndrome (194072) is characterized by susceptibility to Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation; WAGR is a 'contiguous gene syndrome' in which a constitutional deletion on chromosome 11p13 affects several contiguous genes, resulting in a constellation of defects (Schmickel, 1986; Park et al., 1993). Meadows et al. (1974) described a family in which the mother had congenital hemihypertrophy (235000) and 3 of her children had Wilms tumor. A fourth child had a urinary tract anomaly. In 1 of the children the Wilms tumor was bilateral and in a second it was multicentric. Bond (1975) found associated congenital anomalies in 5 of 11 cases of bilateral Wilms tumor and in only 3 of 76 cases of unilateral Wilms tumor. Beckwith (1998) provided useful data on the age at diagnosis of the first Wilms tumor in cases of syndrome-associated WT. Among 121 cases of Beckwith-Wiedemann syndrome (BWS; 130650), 96% were diagnosed by age 8 years; the oldest BWS patient had WT detected at 10 years, 2 months. Among 203 patients with hemihyperplasia, 94% were detected by age 8; the oldest HH patient had WT detected at 12 years, 4 months. Among 61 WAGR patients, Wilms tumor was detected in 98% by age 6 years; the oldest WAGR patient had WT detected at 7 years, 3 months. Among 52 patients with Denys-Drash syndrome (DDS; 194080), WT was detected in 96% by age 5 years; the oldest DDS patient had WT detected at 6 years of age.
Schumacher et al. (1997) identified 19 hemizygous WT1 gene mutations/deletions in tissue samples from 64 patients. The histology of the tumors with mutations was stromal-predominant in 15, triphasic in 3, blastemal-predominant in 1, and unknown in 2 cases. ... Schumacher et al. (1997) identified 19 hemizygous WT1 gene mutations/deletions in tissue samples from 64 patients. The histology of the tumors with mutations was stromal-predominant in 15, triphasic in 3, blastemal-predominant in 1, and unknown in 2 cases. Among 21 patients with stromal-predominant tumors, 15 had WT1 mutations and 10 of these were present in the germline. Of the patients with germline alterations, 6 had associated genitourinary (GU) tract malformations and a unilateral tumor, 2 had a bilateral tumor and normal GU tracts, and 2 had a unilateral tumor and normal GU tracts. Three mutations were tumor-specific and were found in patients with unilateral tumors without genital tract abnormalities. These data demonstrated the correlation of WT1 mutations with stromal-predominant histology, suggesting that a germline mutation in WT1 predisposes to the development of tumors with this histology. Twelve mutations were nonsense mutations resulting in truncation at different positions in the WT1 protein, and only 2 were missense mutations. Of the stromal-predominant tumors, 67% showed loss of heterozygosity, and in 1 tumor a different somatic mutation in addition to the germline mutation was identified. Thus, in a large proportion of a histopathologically distinct subset of Wilms tumors, the classic 2-hit inactivation model, with loss of a functional WT1 protein, is the underlying cause of tumor development.
Haber et al. (1990) described a sporadic, unilateral Wilms tumor in which 1 allele of the WT1 candidate gene contained a 25-bp deletion spanning an exon-intron junction and leading to aberrant mRNA splicing and loss of 1 of ... Haber et al. (1990) described a sporadic, unilateral Wilms tumor in which 1 allele of the WT1 candidate gene contained a 25-bp deletion spanning an exon-intron junction and leading to aberrant mRNA splicing and loss of 1 of the 4 zinc finger consensus domains in the protein. The mutation was absent in the affected person's germline, consistent with the somatic inactivation of a tumor suppressor gene. In addition to the intragenic deletion affecting 1 allele, loss of heterozygosity at loci along the entire chromosome 11 indicated an earlier chromosomal nondisjunction and reduplication. Haber et al. (1992) presented evidence that this mutation of the WT1 gene behaves as a dominant negative, suppressing the function of the wildtype protein by a trans-dominant mechanism. They suspected this because the mutated allele was found to be coexpressed with the wildtype allele in a sporadic Wilms tumor. They therefore tested the ability of this mutant WT1 allele, containing an in-frame deletion within the DNA-binding domain, to transform primary baby rat kidney cells. The mutant WT1 gene was found to cooperate with the adenoviral E1A gene in transforming baby rat kidney cells. The wildtype WT1 gene in all of its alternatively spliced forms neither suppressed E1A-induced focus formation nor cooperated with E1A. Ton et al. (1991) demonstrated that the smallest region of overlap between deletions causing Wilms tumor was a 16-kb segment of DNA encompassing one or more of the 5-prime exons of the zinc finger gene located on 11p13, together with an associated CpG island. This supported the authenticity of the zinc finger gene as the disease locus. Kakati et al. (1991) described a family in which a son had bilateral WT and an extra ring chromosome in the lymphocytes and in kidney tissue. The size of the ring varied considerably from cell to cell. A daughter had unilateral WT and an abnormal clone containing a small ring chromosome in PHA-stimulated and EBV-transformed lymphocytes. The mother, who was unaffected, had a karyotype similar to that of the daughter with WT. Kakati et al. (1991) hypothesized that the son's large ring chromosome was an amplified form of the small ring inherited from the mother. Chromosome 11 was cytogenetically normal in all cells examined in the affected children and the unaffected mother. Varanasi et al. (1994) analyzed the structural integrity of the entire WT1 gene in 98 sporadic Wilms tumors. By PCR-SSCP, they found that mutations in the WT1 gene are rare, occurring in only 6 tumors analyzed. In 1 sample, 2 independent intragenic mutations inactivated both WT1 alleles, providing a singular example of 2 different somatic alterations restricted to the WT1 gene. The data, together with the previously ascertained occurrence of large deletions/insertions in WT1, defined the frequency at which the WT1 gene is altered in sporadic tumors. Nordenskjold et al. (1995) screened 27 cases of 46,XY females with gonadal dysgenesis who had previously been screened for and found not to carry SRY gene mutations (480000) to determine whether isolated gonadal dysgenesis might be due to WT mutations. Using denaturing gradient gel electrophoresis, they found a heterozygous point mutation in exon 8 in 1 of these patients: arg366-to-his, which had previously been described in a case of Denys-Drash syndrome (607102.0004). Reevaluation of the clinical data confirmed the diagnosis of Drash syndrome. Based on these results, Nordenskjold et al. (1995) concluded that isolated gonadal dysgenesis is not caused by mutations in the WT1 gene. White et al. (2002) identified 2 nonconservative single base changes in the GPC gene (300037.0006-300037.0007) in Wilms tumor tissue only, implying a possible role of GPC3 in Wilms tumor development. Lu et al. (2002) studied 18 cases of Wilms tumor with a novel gene-expression profiling method that targets individual chromosomes: comparative expressed sequence hybridization (CESH). Relative overexpression of genes on the long arm of chromosome 1 was shown in all tumors that subsequently relapsed, but in none of those from patients in remission. Anglesio et al. (2004) analyzed the HACE1 gene (610876), which is located 50 kb downstream of the chromosome 6q21 breakpoint of a nonconstitutional t(6;15)(q21;q21) rearrangement in sporadic Wilms tumor. Although the HACE1 locus was not directly interrupted by the translocation in the index Wilms case, HACE1 expression was markedly lower in tumor tissue compared with adjacent normal kidney. HACE1 expression was virtually undetectable in the SK-NEP-1 Wilms tumor cell line and in 4 of 5 additional primary Wilms tumor cases compared with patient-matched normal kidney. There was no evidence of HACE1 mutation or deletion, but hypermethylation of 2 upstream CpG islands correlated with low HACE1 expression in tumor samples. Slade et al. (2010) identified a constitutional de novo balanced translocation t(5;6)(q21;q21) in a boy who developed bilateral Wilms tumor at age 6 months. Breakpoint analysis showed that the translocation transected intron 6 of the HACE1 gene. Further analysis of the HACE1 gene in 450 individuals with Wilms tumor identified 1 patient with a constitutional truncating mutation (W364X) who inherited the mutation from her unaffected mother, suggesting either reduced penetrance or that the mutation was an unrelated finding. Slade et al. (2010) concluded that abrogation of HACE1 activity may predispose to the development of Wilms tumor, although HACE1 mutation is rare and makes only a small contribution to disease incidence. In 2 brothers who both developed Wilms tumor and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations (600185.0027; 600185.0031). In 51 Wilms tumors tested for both gene copy alterations and intragenic mutations, Rivera et al. (2007) found inactivation of the WTX gene (300647) in approximately one-third. Tumors with WTX mutations lack WT1 mutations. In contrast to autosomal tumor suppressor genes, WTX is inactivated by a monoallelic 'single-hit' event targeting the single X chromosome from males and the active X chromosome from females. Regev et al. (2008) reported maternal transmission of a nonsense mutation in the WT1 gene (607102.0027). The mother had Wilms tumor in infancy and decreased fertility in adulthood, and her son displayed genitourinary abnormalities, including glandular hypospadias with chordee and bilateral undescended testes, gonadal dysgenesis with gonadoblastoma foci, and intraabdominal Mullerian derivatives. The boy also had ventricular septal defect by echocardiography; no Wilms tumor was detected up to 6 years of age. Regev et al. (2008) stated that the nonsense mutation demonstrates the lack of correlation between genotype/phenotype and mutation position in the WT1 gene, the presence of intrafamilial variability, and the effect of gender on severity of genitourinary anomalies. Royer-Pokora et al. (2010) described the establishment and characterization of long-term cell cultures derived from 5 individual Wilms tumors with WT1 mutations. Three of these tumor cell lines also had CTNNB1 (116806) mutations and an activated canonic Wnt (164820) signaling pathway as measured by beta-catenin/T cell-specific transcription factor transcriptional activity. Four lines showed loss of heterozygosity of chromosome 11p due to mitotic recombination in 11p11. Gene expression profiling revealed that the WT cell lines were highly similar to human mesenchymal stem cells (MSCs), and FACS analysis demonstrated the expression of MSC-specific surface proteins CD105 (ENG; 131195), CD90 (THY1; 188230), and CD73 (NT5E; 129190). The stem cell-like nature of the WT cells was further supported by their adipogenic, chondrogenic, osteogenic, and myogenic differentiation potentials. By generating multipotent mesenchymal precursors from paraxial mesoderm in tissue culture using embryonal stem cells, gene expression profiles of paraxial mesoderm and MSCs were described. Using these published gene sets, the authors found coexpression of a large number of genes in WT cell lines, paraxial mesoderm, and MSCs. Lineage plasticity was indicated by the simultaneous expression of genes from the mesendodermal and neuroectodermal lineages. The authors concluded that WTs with WT1 mutations have specific traits of paraxial mesoderm, which is the source of kidney stromal cells.