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Neuroblastoma

Late Effects

Multiple genes and chromosomal loci are implicated in the development of Wilms tumor. This reflects the:

• Complexity of nephrogensis
• Two distinct histologic precursors [ILNR, PLNR]
• Histologic diversity of WTs

Chromosome 11p13 and WT-1 gene

• First locus implicated in the development of WT.
• Small deletion on Chromosome 11 detected in tumor cells.
• Site of constitutional deletions in patients with WAGR syndrome.

• WT-1 gene:
  • Gene that encodes a transcription factor important in normal kidney and gonadal development.
  • Transcription factor with a zinc finger protein structure.
• Patients with Denys-Drash syndrome found to have constitutional inactivating point mutations in WT-1 while their WTs consistently showed loss of their remaining normal WT-1 allele.
• The incidence of WT is higher and the phenotypic effects more severe in Denys-Drash syndrome where the point mutations are thought to act as dominant negative mutations creating a dysfunctional protein that interferes with the product of the non-mutated allele.
• Mechanism is different in WAGR syndrome where WT-1 is deleted. The absence of WT-1 is thought to result in a failure to arrest blastemal growth.
• WT-1 alterations strongly linked to the development of WT in syndromic cases, but role in the development of sporadic WT appears to be limited.

Chromosome 11p15

• Second WT locus (WT2) has been localized to chromosome 11p15.
• Beckwith-Wiedemann syndrome also maps to this location.
• Initial evidence from the linkage of the familial BWS cases to this locus.
• This region also shows loss of heterozygosity in up to 40% of sporadic WTs.
• The lost allele is almost always maternal.
• Results suggest that the responsible genes in this locus are imprinted.
• Loss of a growth suppressing maternal gene or over expression of a growth promoting paternal gene could promote tumor development.

The candidate gene for sporadic WT (there may be more than one gene involved] has not yet been identified.

Wilms tumor at the Atlas of Genetics and Cytogenetics in Oncology and Haematology

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