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Wilms Tumor

 

 

Genetics

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.

 

Links:

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

Wilms tumor at the National Cancer Institute

 

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