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Wilms Tumor




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


Complex genetic changes are present in Wilms tumors:

  • Trisomies 8, 12, and 18 common
    • 11p deletions in 20% of cases
    • trisomy 12 in 25%
    • del(16q) in 20%
  • Loss of heterozygosity (LOH) at 1p, 7p and 16q.


Wilms Tumor 1 gene (WT 1):

  • The WT 1 gene is located on the short arm of chromosome 11 (11p13)
  • This is the first locus implicated in the development of WT and a small deletion on chromosome 11 is detected in tumor cells.
  • This is the 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.


Wilms Tumor 2 gene (WT 2):

  • A second WT locus (WT2) has been localized to chromosome 11p15.5
  • 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.


Wilms Tumor gene on the X chromosome (WT X):

  • A third gene, WTX has been identified on the X chromosome
  • WTX:
    • plays a role in normal renal development
    • mutations identified in 17% of Wilms tumors
    • is inactivated in one third of Wilms tumors


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


Prognosis and cytogenetics:

Tumor-specific Loss of Heterozygosity (LOH) for specific chromosomes is a prognostic factor in Wilms tumor.

  • Tumor-specific LOH for either chromosome 1p or 16q is associated with a worse
    outcome in FH Wilms tumors, relative to those without LOH.
  • LOH for chromosome 1p seen in about 11% of Wilms tumors and is associated with poorer outcome.
    • Tumor-specific LOH 1p is associated with a significantly worse outcome for Stage II patients but not for Stage III/IV (more intense chemotherapy in latter group overcomes negative effect of LOH 1p).
  • Tumor-specific loss of 16q in 20% of patients and associated with a poorer two-year
    Relapse Free survival (RFS).
  • LOH for chromosome for both 1p and 16q in Stage I and II FH Wilms tumor is associated with a poorer prognosis with a greater risk of relapse and mortality.
  • Stage I or II FH tumors with either LOH 1p or LOH 16 q alone have a lesser risk for relapse than those with both LOH 1p and 16q

Reports suggest that anaplasia may be associated with mutation and or over expression of p53.


MicroRNA- Processing Gene Mutations

  • Approximately 15% of Wilms tumors have microRNA-processing gene mutations.
  • The most common is DROSHA (found in 12%) but other microRNA-processing genes include DGCR8, DICER1, XPO5, TARBP2 and DISL32.  These mutations often occur with mutations in SIX1 and SIX2 which encode transcription factors critical to embryonic renal development.



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

Wilms tumor at the National Cancer Institute


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