7491

WT2

ADCR|MTACR1;Wilms tumor 2;WT2;Wilms tumor 2

-

11p15.5

other

The molecular genetic characterization of Wilms' tumor has played a prominent role in advancing our knowledge of the genetic aspects underlying the development of cancer in general. Unlike the genetic mechanism leading to the development ofretinoblastoma, an embryonal tumor of childhood affecting the retina, which onlyrequires the inactivation of one single gene, the biological pathways leading tothe development of Wilms' tumor are complex and likely involve several genetic loci. These include two genes on chromosome 11p; one on chromosome 11p13 (the Wilms' tumor suppressor gene WT1) and the other on chromosome 11p15 (the putative Wilms' tumor suppressor gene WT2). In addition to these two genes, loci at 1p, 7p, 16q, 17p (the p53 tumor suppressor gene), and 19q (the putative familial Wilms' tumor gene FWT2) are also believed to harbor genes involved in the biology of Wilms' tumor. Herein these loci are reviewed and their clinical significance is summarized.

BACKGROUND: Wilms' tumors are highly malignant tumors of the kidneys and are among the most frequent solid tumors of childhood, which are diagnosed for the most part before the 5th year. Various congenital anomalies are associated with a genetic predisposition and thus an increased risk of developing a Wilms' tumor. PATIENTS AND METHODS: As part of a retrospective analysis, the records from 1965to 2003 of 66 patients with histologically confirmed Wilms' tumor were reviewed.The aim of this study was to determine the incidence and type of different urogenital malformations as well as the genetic mutations and overall survival in this patient group. RESULTS: The patient cohort comprised 66 patients with histologically confirmed Wilms' tumor: 35 male patients (53%) and 31 female patients (47%). The overall survival after 10 years was 89.4%. ALL patients underwent radical nephrectomy: transperitoneal approach in 63 and lumbar approach in 3 patients. Eleven (16.7%) patients had diverse urogenital anomalies. A cytogenetic investigation was performed in 38 patients that revealed no pathological findings. The results of molecular genetic testing of tumor specimens were available for seven patients: a genetic mutation was detected in one case (heterozygous mutation R394 in exon 9 of the WT1 gene) which had already been described in the literature in conjunction with Denys-Drash syndrome. Hemihypertrophy with Beckwith-Wiedemann syndrome was present in two (3%) patients. CONCLUSION: In patients with urogenital malformations and Wilms' tumor, it would be important to carry out further molecular genetic testing to identifypossible WT1 gene mutations. Close interdisciplinary cooperation between urologists, specialists in human genetics, and pediatricians is imperative.

WT1 (Wilms' tumor gene 1) overexpression is implicated in the prognosis of acuteleukemia. The purpose of this study was to investigate WT1 expression and its clinical implication in childhood acute leukemia (AL) in Chinese population. Bone marrow specimen from 200 children at different stages of acute leukemia and from21 children without leukemia were studied. The WT1 expression at diagnostic marrow specimen in both acute myeloid leukemia (AML) and acute lymphoid leukemia(ALL) was higher than control group, whereas WT1 expression in AML was higher than in ALL, and WT1 expression level in relapse in ALL increased more significantly than in AML. The WT1 expression level showed positive correlation with the hypodiploidy and BCR-ABL fusion gene in acute leukemia. A rapidly decrease of WT1 expression level predicted a good response to the induction therapy and low expression of WT1 correlates with remission status. This study suggested that WT1 expression levels in acute leukemia can potentially be a marker for evaluating therapeutic efficacy, correlating with monitoring minimal residue disease, and predicting hematological relapse in children acute leukemia.

PURPOSE OF REVIEW: To review the 2009/2010 literature on pediatric genitourinarytumors and highlight the most significant publications. RECENT FINDINGS: New techniques such as gene expression profiling, PET, nephron-sparing surgery, and stem cell transplantation are being incorporated into contemporary treatments for pediatric patients with genitourinary tumors. Biologic markers are increasingly being used to help with risk stratification of patients. WT1 mutation and 11p15 loss of heterozygosity have been associated with relapse in very low-risk Wilms tumors treated with surgery alone and may help reduce the use of chemotherapy insome children. Discussion continues on the use of fusion gene status to risk stratify alveolar rhabdomyosarcoma. Meta-analysis of the use of high-dose chemotherapy with autologous hematopoetic stem cell rescue in patients with relapsed Wilms tumor and rhabdomyosarcoma suggests that some patients may benefit more from conventional salvage chemotherapy. New agents are needed for patients with high-risk and relapsed disease to improve outcomes. SUMMARY: In general, the prognosis for patients with pediatric genitourinary tumors is favorable. The elucidation of the molecular abnormalities in these tumors is determining risk stratification, treatment strategies, and candidates for new drug development.

The Wilms tumor 1 (WT1) gene is currently in focus by pediatric nephrologists asits mutations are associated with nephrotic syndrome, especially as part of complex clinical entities like Denys-Drash or Frasier syndrome. Renal failure may also develop in young WAGR patients, whose condition is attributed to a deletionat chromosomal region 11p13. However, only limited data exist on WT1 microdeletions. A 30-year-old male patient, with a history of genital malformations, a Wilms tumor manifested during the treatment of acute lymphoid leukemia (ALL) at the age of 4, and a cerebellar angioblastoma, was referred with proteinuria and a reduced glomerular filtration rate (GFR). Kidney biopsy revealed FSGS. Although ALL WT1 exons were amplified with polymerase chain reaction (PCR) and sequenced, none of them showed a mutation. However, an formalin-fixed, paraffin- embedded (FFPE) tissue sample of the patient's childhood Wilms tumor showed WT1- positivity restricted to the renal tumor cells, so the WT1 gene was investigated further. Using quantitative reverse transcription PCR (qRT-PCR), the gene was found to be present in only one copy in the patient's genomic DNA sample, while both copies were detected in both parents. In the patient's sister, the proximal region of WT1 was shown to have an extra copy. Evidence suggests that a heterozygous microdeletion of the gene WT1 is responsible for the patient's disease. It seems reasonable to assume a possible abnormality affecting meiotic crossing over at the WT1 locus in one of the parents.

Wilms' tumor is a childhood nephroblastoma that is postulated to arise through the inactivation of a tumor suppressor gene by a two-hit mechanism. A candidate 11p13 Wilms' tumor gene, WT1, has been cloned and shown to encode a zinc finger protein. Patients with the WAGR syndrome (Wilm's tumor, aniridia, genitourinary abnormalities, and mental retardation) have a high risk of developing Wilms' tumor and they carry constitutional deletions of one chromosome 11 allele encompassing the WT1 gene. Analysis of the remaining WT1 allele in a Wilms' tumor from a WAGR patient revealed the deletion of a single nucleotide in exon 7. Thismutation likely played a key role in tumor formation, as it prevents translationof the DNA-binding zinc finger domain that is essential for the function of the WT1 polypeptide as a transcriptional regulator.