Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene

Abstract

Genes identified as being mutated in Wilms' tumour include TP53, a classic tumour suppressor gene (TSG); CTNNB1 (encoding β-catenin), a classic oncogene; WTX, which accumulating data indicate is a TSG; and WT1, which is inactivated in some Wilms' tumours, similar to a TSG. However, WT1 does not always conform to the TSG label, and some data indicate that WT1 enhances cell survival and proliferation, like an oncogene. Is WT1 a chameleon, functioning as either a TSG or an oncogene, depending on cellular context? Are these labels even appropriate for describing and understanding the function of WT1?

Figure 1. WT1 mutations observed in Wilms’ tumour and acute myeloid leukaemia (AML)

a ∣ WT1 gene and protein structure. Blue shading indicates alternatively spliced domains. Four isoforms result from exon 5 and KTS alternative splicing. b ∣ Germline mutations observed in patients with Wilms’ tumour-associated phenotypes. Similar mutations are observed somatically in tumours. c ∣ Somatic mutations observed in AML. Location of gene mutations are indicated by blue (insertion or deletions and frameshift mutations), purple (nonsense mutations), green (missense mutations) and orange (splice site mutations) ovals. Predicted mutant proteins are shown for deletion mutations. Asterisk indicates reduced KTS⁺/KTS⁻ isoform ratio as a result of IVS9 splice site mutations. ZNF, zinc finger domain. Data from REFS 61,–.

Figure 2. WTX mutations in Wilms’ tumour and osteopathia striata congenita with cranial sclerosis (OSCS)

The full-length WTX protein possesses two phosphatidylinositol(4,5)-bisphosphate (PtdIns(4,5)P₂) binding domains that mediate the localization of the protein to the plasma membrane, whereas the smaller isoform lacks these domains and localizes primarily to the nucleus^–. Both WTX isoforms contain a β-catenin binding domain. Additionally, three adenomatous polyposis coli (APC) binding domains are in the full-length protein ; one of these is truncated in the shorter WTX isoform^,. As denoted, mutations of known functional importance include whole-gene deletions and mutations (blue ovals) resulting in truncated protein products (lines). Blue shading denotes a region of the protein present only in the larger isoform owing to alternative intra-exonic splicing. aa, amino acid.

Figure 3. WT1 expression during kidney and myeloid differentiation, and phenotypic consequences of altered expression or gene ablation

a ∣ WT1 loss of function in the developing kidney results in cell death when ablated in early metanephric mesenchyme or results in a disruption of differentiation if ablated in committed condensed mesenchyme^,. The observation of WT1 mutations in Wilms’ tumours implies that its loss — in conjunction with other alterations — ultimately results in proliferation (tumours). b ∣ During haematopoiesis, loss of WT1 retards cell proliferation and/or differentiation. Exogenous expression of WT1 in the CD34⁺CD38⁺ committed precursor population results in quiescence, whereas such expression in the more differentiated common myeloid progenitors results in proliferation^–). Ectopic expression of WT1 in long-term haematopoietic stem cells results in reduced haematopoiesis. As with Wilms’ tumour, the observation of WT1 mutations in some leukaemias links its loss at some stage of haematopoiesis with a proliferative phenotype.