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
- 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.