Wilms tumor genetics: Mutations in WT1, WTX, and CTNNB1 account for only about one‐third of tumors

Abstract

Wilms tumor is genetically heterogeneous, and until recently only one Wilms tumor gene was known, WT1 at 11p13. However, WT1 is altered in only ~20% of Wilms tumors. Recently a novel gene, WTX at Xq11.1, was reported to be mutated in Wilms tumors. No overlap between tumors with mutations in WTX and WT1 was noted, suggesting that WT1 and WTX mutations could account for the genetic basis of roughly half of Wilms tumors. To assess the frequency of WTX mutations and their relationship to WT1 mutations in a larger (n = 125) panel of Wilms tumors which had been thoroughly assessed for mutations in WT1, we conducted a complete mutational analysis of WTX that included sequencing of the entire coding region and quantitative PCR to identify deletions of the WTX gene. Twenty-three (18.4%) tumors carried a total of 24 WTX mutations, a lower WTX mutation frequency than that previously observed. Surprisingly, we observed an equivalent frequency of WTX mutations in tumors with mutations in either or both WT1 and CTNNB1 (20.0%) and tumors with no mutation in either WT1 or CTNNB1 (17.5%). WTX has been reported to play a role in the WNT/β-catenin signaling pathway, and, interestingly, WTX deletion/truncation mutations appeared to be rare in tumors carrying exon 3 mutations of CTNNB1, encoding β-catenin. Our findings indicate that WT1 and WTX mutations occur with similar frequency, that they partially overlap in Wilms tumors, and that mutations in WT1, WTX, and CTNNB1 underlie the genetic basis of about one-third of Wilms tumors.

Canonical WNT signalling determines lineage specificity in Wilms tumour

“…However, the majority of the CTNNB1 mutations in tumours with WTX alterations were found in exon 7 or 8, which unlike exon 3 mutations, do not affect the b-catenin serine threonine phosporylation-binding site and therefore may not lead to constitutive b-catenin activation. Mutations in CTNNB1 and WTX were therefore proposed to be not functionally redundant (Ruteshouser et al, 2008), supporting the notion that b-catenin and WTX act in a common pathway. Alternatively, WTX has been independently reported as an APC-interacting protein controlling the subcellular distribution of APC between the cell membrane and the microtubule of epithelial cells (Grohmann et al, 2007), suggesting another tumour suppressor function of WTX independent of WNT signalling.…”

“…WTX (also called AMER1) has been reported to be deleted or mutated in 7-29% of WTs (Rivera et al, 2007;Perotti et al, 2008;Ruteshouser et al, 2008). WTX appears to act as an unusual tumour suppressor gene, in which it is inactivated by one-hit mutational events: mutations in the single X chromosome in tumours from males and the active X chromosome in tumours from females cause inactivation of this gene (Rivera et al, 2007;Perotti et al, 2008;Ruteshouser et al, 2008). Recently, WTX was found to form a complex with AXIN, APC (adenomatous polyposis coli) and b-catenin in the cytoplasm (Grohmann et al, 2007;Major et al, 2007).…”

“…WTX was shown to antagonize WNT/b-catenin signalling, as WTX interacted directly with b-catenin to promote its ubiquitination and degradation (Major et al, 2007). Although two studies have found that mutations in WTX and CTNNB1 were mutually exclusive in WTs (Rivera et al, 2007;Perotti et al, 2008), one study showed that WTX mutations partially overlapped with CTNNB1 mutations in WTs (Ruteshouser et al, 2008). However, the majority of the CTNNB1 mutations in tumours with WTX alterations were found in exon 7 or 8, which unlike exon 3 mutations, do not affect the b-catenin serine threonine phosporylation-binding site and therefore may not lead to constitutive b-catenin activation.…”

Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants

“…WTX mutations exist in tumors with and without b-catenin mutations (Ruteshouser et al, 2008), whereas b-cartenin mutations are found almost exclusively in the presence of loss-of-function mutations of WT1 (Maiti et al, 2000). We previously showed that WT1 inhibited the transcriptional function of both wild-type and constitutively active, gain of function b-catenin alleles .…”

“…Without a homologue on the Y chromosome and subjected to X inactivation, WTX is a single copy tumor suppressor; hence loss or mutation of a single allele appears to be sufficient to allow tumor formation. Analysis of a small panel of Wilms tumors initially suggests that WT1 and WTX mutations are mutually exclusive, while later studies with a larger sets of tumors shows that WTX mutations (7-18% of cases) occurs at a similar frequency as WT1 mutations and WT1 and WTX mutations can be found in the same tumor (Perotti et al, 2008;Ruteshouser et al, 2008;Wegert et al, 2009). WTX mutations are rare in other tumor types (Chung et al, 2008;Owen et al, 2008;Yoo et al, 2009).…”