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Frequency and Heritability of WT1 Mutations in Nonsyndromic Wilms' Tumor Patients: A UK Children’s Cancer Study Group Study

From the Sections of Paediatric Oncology and Cancer Genetics, Institute of Cancer Research, Royal Marsden Hospital; and Paediatric Oncology Unit, The Royal Marsden Hospital, Sutton, Surrey, United Kingdom

Address reprint requests to Kathy Pritchard-Jones, MD, Paediatric Oncology Unit, The Royal Marsden NHS Trust, Downs Rd, Sutton, Surrey, SM2 5PT United Kingdom; e-mail: Kathy.Pritchard-Jones{at}icr.ac.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Constitutional WT1 mutations in patients with Wilms' tumor (WT) have specifically been associated with genitourinary abnormalities, such as cryptorchidism and hypospadias. We sought to ascertain the frequency and heritability of constitutional WT1 mutations in nonsyndromic WT patients.

PATIENTS AND METHODS: Constitutional DNA from 282 patients treated at seven United Kingdom Children's Cancer Study Group centers was screened for WT1 mutations using heteroduplex analysis. Bidirectional sequencing was used to confirm the mutation and to analyze the corresponding parental DNA samples.

RESULTS: Five different constitutional WT1 mutations were identified in six children. Mutations in four patients were confirmed to be de novo, and all five mutations are predicted to produce truncated protein. The WT1 mutation group had a young median age at diagnosis of 13.8 months, compared with 34.9 months in the group in whom no WT1 mutations were found; four were female and two were male; and all tumors were of favorable histology. The three tumors with known histologic subtype were stromal-predominant. Contrary to expectation, four of six mutations occurred in children with unilateral tumors without any associated genitourinary abnormality.

CONCLUSION: Constitutional WT1 mutations occur with a low frequency (2.1%; 95% CI, 0.8% to 4.6%) in nonsyndromic WT patients. Most mutations occurred in children with unilateral WT without associated genitourinary abnormalities, creating difficulties in identifying individuals with germline mutations on phenotype alone. Two factors that may indicate that an individual is carrying a germline WT1 mutation are an early age of onset and stromal-predominant histology of the WT.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Wilms' tumor (WT), or nephroblastoma, is the most common malignant renal tumor in childhood, accounting for approximately 8% of all pediatric cancers. The Wilms' tumor gene (WT1) locus was first identified in patients with WT, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome¹ who were found to have constitutional deletions of 11p13.² Loss of heterozygosity at 11p13 in WT tissue supported the idea that a tumor suppressor gene important in the development in WT was located at 11p13.^3-6 The WT1 gene was identified in 1990^7,8 and found to encode a transcription factor of the zinc-finger family, which is critical to the normal development of the kidney and gonads.⁹ The WT1 gene consists of 10 exons, with exons 1 to 6 encoding an N-terminal proline- and glutamine-rich transactivational domain, and exons 7 to 10 encoding a C-terminal zinc-finger domain involved in DNA binding.^7,10 An alternative CUG initiation codon 204 bp upstream of the normal start codon generates larger WT1 proteins of 60 to 62 kd.¹¹ Mice with a specific absence of the CUG-initiated WT1 isoforms develop normally, have normal genitourinary development, and are fertile.¹²

Constitutional WT1 mutations have been identified in individuals with WAGR syndrome (MIM 194072), Denys-Drash syndrome (DDS; nephropathy caused by diffuse or focal mesangial sclerosis, genitourinary abnormalities, WT; MIM 194080),^13-16 and Frasier syndrome (focal and segmental glomerulosclerosis, pseudohermaphroditism, gonadoblastoma; MIM 136680).^17-19 Germline WT1 mutations have also been identified in four pedigrees of familial WT.^20-23 However, these represent only a small proportion of the more than 100 pedigrees described worldwide. Furthermore, occurrences of transmission of a WT1 mutation from an unaffected carrier parent have been described in apparently sporadic cases of WT. Individuals with isolated diffuse mesangial sclerosis^24-26 or bilateral WT without any associated genitourinary abnormalities or nephropathy,²⁷ and a few children with unilateral WT and no genitourinary abnormalities,²⁷ are also reported to carry germline WT1 mutations. However, the incidence of WT1 mutations in individuals with these phenotypes is uncertain. It is therefore difficult to identify individuals carrying germline WT1 mutations on phenotype alone.

Two previously published studies have examined constitutional WT1 mutations in WT. The first study sought to determine the frequency of constitutional WT1 mutations in 201 patients with WT and to identify clinical anomalies associated with these mutations.²⁸ The study population was selected to enrich for children likely to have a genetic predisposition to developing WT; that is, those with bilateral tumors, associated genitourinary anomalies or nephrogenic rests, a family history of WT, or a history of second primary cancers after treatment for WT. They excluded children with known WT predisposition syndromes, such as WAGR, DDS, Beckwith-Wiedemann syndrome (BWS), or known chromosomal disorders (trisomy 21, Turner's syndrome). Eight of 201 patients (4.0%) were identified as carrying constitutional WT1 mutations, seven of whom were boys with cryptorchidism (n = 28; four of these also had hypospadias). None of the children with unilateral WT and no associated anomalies (n = 56) carried constitutional WT1 mutations. They concluded that germline WT1 mutations in children with WT are associated with genitourinary anomalies, especially cryptorchidism and/or hypospadias, and that patients with WT and no genitourinary anomalies are at a low risk of carrying WT1 mutations. A second study examined the correlation between constitutional WT1 mutations and WT of stromal-predominant histology.²⁷ Ten of 21 patients (47.6%) with stromal-predominant histology WT carried WT1 mutations in the germline, as well as in tumor tissue. Of these 10 individuals with constitutional WT1 mutations, six had genital tract malformations and unilateral tumors, two had bilateral tumors and normal genitourinary tracts, and two had unilateral tumors and normal genitourinary tracts. This study demonstrates that there is a correlation between WT1 mutations and stromal-predominant histology WT, suggesting that constitutional WT1 mutations predispose to this histologic subtype. It also highlights the fact that constitutional WT1 mutations can occur in patients with unilateral tumors and without any associated genitourinary abnormality. No analysis of parental DNA was carried out in either of these studies.

To date, no attempt has been made to systematically determine the frequency of germline WT1 mutations in children with WT. Our study aims to determine the frequency of constitutional WT1 mutations in children with nonsyndromic WT in the United Kingdom, and to investigate the heritability of these mutations. In this instance, nonsyndromic WT patients exclude those with recognized WT predisposition syndromes, such as WAGR, DDS, Frasier syndrome, BWS, and familial WT.

	PATIENTS AND METHODS

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Samples
This research was approved by the London Multicenter Research Ethics Committee and the United Kingdom Children's Cancer Study Group (UKCCSG). Blood samples were obtained as part of an ongoing sample collection of constitutional DNA from all children with a diagnosis of a renal tumor under treatment or follow-up at participating UKCCSG centers. Blood samples were also requested from both parents. Written informed consent was obtained from parents and from affected individuals age 16 years or older. If a WT1 mutation was identified, the family was informed by the treating oncologist. The mutation was confirmed in a newly ascertained sample and genetic counseling was provided by the local Clinical Genetics Service. The study aims to identify genes predisposing to WT and investigate their phenotypic associations and heritability. Analysis of constitutional WT1 mutations forms the first stage of this project.

Over the period 1997 to 2002 (60 months), blood samples from 334 children with a diagnosis of a renal tumor and from 527 parents had been received from 10 UKCCSG centers. Samples for this study were restricted to those obtained from the seven UKCCSG centers that were routinely approaching all patients on treatment or follow-up for WT at their hospital during this period. The seven United Kingdom centers (number of samples screened appear in parentheses) were Great Ormond Street Hospital, London (73); St James's University Hospital, Leeds (57); Royal Victoria Infirmary, Newcastle (53); Royal Marsden Hospital, Sutton (33); Southampton General Hospital, Southampton (32); Royal Hospital for Sick Children, Glasgow (24); and Addenbrooke's Hospital, Cambridge (21).

The following information was requested for each patient: age at diagnosis, laterality of tumor, histologic subtype, presence of congenital abnormalities in the patient, and family history of renal anomalies or early onset cancer (younger than 50 years). The following patients were excluded: children with a diagnosis of renal tumor other than WT and those with a definite WT predisposition syndrome or family history of WT. The cohort for constitutional WT1 mutational analysis therefore comprised 293 children with apparently sporadic WT. Children with bilateral WT and isolated congenital abnormalities, including hemihypertrophy without stigmata of BWS, were included. Eleven patients were subsequently excluded because their DNA samples failed to amplify in 20% or more of the mutation detection analyses, meaning that 282 children were included in the final series. Blood samples were also taken from parents when possible and were obtained from both parents in 177 instances (62.8%). Control DNA from 288 randomly selected individuals was obtained from the European Collection of Cell Cultures Human Random Control DNA panels. These samples were used to evaluate the frequencies of G(–9)R and P181S in the United Kingdom population.

Mutation Detection
DNA was extracted from peripheral-blood lymphocytes using the sucrose lysis method. All 10 exons of the WT1 gene were amplified individually by polymerase chain reaction PCR. Exon 1 required amplification in three overlapping fragments using a GC-rich amplification system; all other exons were amplified by one specific primer pair. A sample was deemed adequately screened for WT1 mutation if greater than 80% of the analyses were successful. Primers were designed using Primer3 software (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi). Primer sequences and conditions are available on request. Before setting up the PCR reactions, each primer was end-labeled with gamma-phosphorus-32–labeled adenosine triphosphate using polynucleotide kinase (Cambio, Cambridge, UK). Conformation-sensitive gel electrophoresis was carried out according to Ganguly.²⁹ The gels were dried and exposed to autoradiographic film (Hyperfilm; Amersham, Little Chalfont, UK). Data from at least 80% of analyses were available for all patient cases. Bidirectional sequencing was carried out on samples showing a mobility shift on conformation-sensitive gel electrophoresis and on the relevant exon in the parental DNA samples. Constitutional DNA was amplified using PCR, and the PCR products were purified using QIAquick PCR Purification Kit (QIAGEN, Crawley, UK). Sequencing reactions were carried out using DNA Sequencing Kit BigDye Terminator v3.0 Cycle Sequencing Ready Reaction Mix (Applied Biosystems, Warrington, UK). The sequencing product was precipitated using ethanol and sodium acetate, resuspended in 12 µL Hi-Di Formamide (Applied Biosystems) and run on an Applied Biosystems 3100 Genetic Analyzer.

Statistical tests were carried out using StatsDirect software version 2.3.5 (Cheshire, United Kingdom; http://www.statsdirect.com/).

	RESULTS

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Two hundred eighty-two children with nonsyndromic WT were successfully screened for constitutional WT1 mutations. In total, five distinct WT1 mutations were identified in six children; one mutation (R390X) was identified in two separate individuals (Table 1). Three were nonsense mutations (Q74X, R301X, R390X), two of which were in the zinc-finger region, one was a 5-bp insertion (D207fsX219), and one was a splice site mutation (IVS1+1G>A). All five mutations are predicted to result in premature truncation of the protein. In four patient cases, these mutations were confirmed to be de novo. In the remaining two patient cases, only one parental sample was available for testing and this did not carry the mutation. Two of the mutations (R301X, R390X) have been reported previously^30,27; the remaining three are novel mutations.

	DISCUSSION

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Previous descriptions of WT occurring in children with underlying constitutional WT1 mutations have emphasized the well-recognized association with genitourinary malformation.^21,31,28,25 This is expected from the established role of WT1 in normal genitourinary development.^32,9 However, our study of unselected patients shows that of the six children in whom constitutional WT1 mutations were identified, five had no genitourinary abnormalities and one boy had bilateral cryptorchidism and bilateral inguinal hernias. This is in contrast to the results of a previous study,²⁸ in which seven of eight patients with constitutional WT1 mutations were males with cryptorchidism, four of whom also had hypospadias. In total, WT1 mutations were found in 25.0% (seven of 28) of males with cryptorchidism.

The slightly higher incidence (4.0%) of WT1 mutations found in the study of Diller et al²⁸ compared with our study is probably due the selection of their study population to enrich for children likely to have a genetic predisposition to developing WT (ie, those with bilateral tumors,³³ associated genitourinary anomalies^34,25 or nephrogenic rests,³⁵ a family history of WT,³⁶ or a history of second primary cancers after treatment for WT). Their study population therefore contained a high proportion of children with genitourinary malformation (46 of 201; 22.9%). We did not find a strong excess of constitutional WT1 mutations in patients with bilateral tumors (one of 18), similar to the findings (three of 21 patients with bilateral disease had WT1 mutations) reported by Diller et al,²⁸ but in contrast to a study by Huff, which found four of six germline WT1 mutation carriers had bilateral disease.³⁷ If we focus on the group of children with unilateral WT without any congenital anomalies, then four of 250 (1.6%; 95% CI, 0.4% to 4.0%) would have been identified as carrying constitutional WT1 mutations in our study population. These small proportions probably explain why no germline WT1 mutations were detected in the smaller group of 56 children with unilateral WT in the study by Diller et al²⁸ (0%; 97.5% one-sided CI, 0% to 6.4%). It should be noted that the CIs for these studies overlap and that there is unlikely to be significant differences in the contribution of WT1 mutations to either unilateral or bilateral WT in the populations from the United Kingdom and United States.

Two factors that may indicate patients likely to be carrying a constitutional WT1 mutation are an early age of tumor onset and histologic subtype. Our study demonstrates the younger age of onset in those with genetic predisposition due to a WT1 mutation. The median age of diagnosis was 13.8 months in the mutation group (five of six were younger than 24 months of age at diagnosis), compared with 34.9 months in the nonmutation group. The previous study²⁸ also supports this finding, with a median age at diagnosis of 13 months in children identified as carrying constitutional WT1 mutations.

The association of WT1 mutation with WT showing stromal-predominance and heterologous differentiation, particularly into primitive skeletal muscle, has been described.^27,38 However, it must be noted that the prevalence of stromal predominance depends on whether the tumor has been exposed to chemotherapy before nephrectomy. In a study focusing on analysis of WT with stromal-predominant histology, in which the majority of patients had been treated by preoperative chemotherapy, 13 of 21 tumors of this subtype were found to carry somatic WT1 mutations. In 10 of these 13 patients, the mutation was constitutional.²⁷ This correlation between WT1 mutation and stromal-predominant histology was also seen in our study, in which all three patients with germline WT1 mutations in which detailed histologic description was available showed stromal-predominance with prominent differentiation along a rhabdomyoblastic lineage. All had received preoperative chemotherapy. One of these patients was diagnosed as having fetal rhabdomyomatous nephroblastoma on initial biopsy with unchanged histology at delayed nephrectomy.

Five distinct mutations were identified in six individuals. Two of the mutations (R301X, R390X) have been reported previously as both somatic and constitutional WT1 mutations.^27,30 The mutation R301X was identified in the constitutional DNA of female identical twins who developed bilateral and unilateral tumors at the ages of 18 and 19 months, respectively.²⁷ Neither of these children was reported to have any clinical anomalies, but they both had an earlier age of onset compared with the overall median age at diagnosis of 39 months. The mutation R390X was identified previously in the constitutional DNA of a child diagnosed with unilateral WT at 24 months of age, who also had maldescended testes and proteinuria.²⁷ The three previously unreported mutations (IVS1+1G>A, D207fsX219, Q74X) are also predicted to result in truncation of the protein. Given that all five mutations described above are predicted to produce truncated proteins, disrupting or deleting the DNA binding domain of the WT1 protein, it is likely that they are loss-of-function mutations and therefore pathogenic.

Interpreting the pathogenic significance of sequence variations can be difficult. We identified an additional sequence variant in a male child who was diagnosed with bilateral WT at 24 months of age, who was specifically selected for WT1 mutational analysis and was not included in the main cohort. Although the variant, P181S, has been reported previously as a heterozygous mutation in the WT of one patient and as a constitutional mutation in another patient,^27,39 it is not clear if this sequence change is a pathogenic mutation or a polymorphism. This variant was not identified in 280 control samples, suggesting that it may be pathogenic. However, it was inherited from an unaffected father. This amino acid (encoded by codon 181) is conserved in mice, rats, chicks, and alligators, but not in zebrafish or fugu, where it is replaced by serine (the supposedly mutant protein) and threonine, respectively.

This is the first study to provide data on heritability of WT1 mutations. Four of the six mutations were confirmed as being de novo, making it likely that they are pathogenic mutations. De novo mutations will not affect siblings, but they do have implications for offspring of the affected child. It is possible that the lack of heritability of WT1 mutations may be due to decreased fertility in those carrying constitutional WT1 mutations.⁴⁰ However, it remains important to test the parents because rare cases of transmission of WT1 mutations from nonpenetrant parents or rare cases of familial WT as a result of WT1 have been documented. As would be expected with de novo mutations, there was no family history of early-onset cancer or renal disease in the children with germline WT1 mutations.

The phenotypic spectrum associated with constitutional WT1 mutations is broad. This research shows that it may not be easy to identify individuals carrying germline mutations on phenotype alone, and the clinical challenge lies with predicting those likely to carry WT1 mutations when there is no obvious clinical phenotype. Factors that may indicate that an individual is carrying a germline WT1 mutation are an early age of onset, genitourinary abnormalities, bilateral disease, and stromal-predominant histology. The presence of one or more of these criteria could be used as a prioritization strategy for WT1 mutation screening. However, it should be recognized that some WT patients with none of these features might still carry WT1 mutations.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank all of the patients with WT and their parents who contributed samples to this study, the clinicians and research nurses at all the participating UKCCSG centers (and Bristol Children's Hospital for contributing the case with the sequence variant P181S), Jenny Douglas for able technical assistance and the following pediatric pathologists, Iona Jeffrey, MD, St George's Hospital, London, and Neil Sebire, MD, Great Ormond St Hospital, London, United Kingdom, for providing detailed histologic information.

	NOTES

 
Supported in part by Cancer Research UK.

Presented as platform presentations at British Cancer Research Meeting, Bournemouth, UK, July 2-5, 2003, and 35th Congress of the International Society of Paediatric Oncology, Cairo, Egypt, October 8-11, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted February 20, 2004; accepted August 6, 2004.

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