Functional inactivation of the WTX gene is not a frequent event in Wilms’ tumors

Department of Experimental Oncology and Laboratories, Genetic Susceptibility to Cancer Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Oncogene (Impact Factor: 8.46). 05/2008; 27(33):4625-32. DOI: 10.1038/onc.2008.93
Source: PubMed


For many years the precise genetic etiology of the majority of Wilms' tumors has remained unexplained. Recently, the WTX gene, mapped to chromosome Xq11.1, has been reported to be lost or mutated in approximately one-third of Wilms' tumors. Moreover, in female cases, the somatically inactivated alleles were found to invariantly derive from the active chromosome X. Consequently, WTX has been proposed as a 'one-hit' tumor suppressor gene. To provide further insights on the contribution of WTX to the development of the disease, we have examined 102 Wilms' tumors, obtained from 43 male and 57 female patients. Quantitative PCR analyses detected WTX deletions in 5 of 45 (11%) tumors from males, whereas loss of heterozygosity at WTX-linked microsatellites was observed in 9 tumors from 50 informative females (19%). However, in the latter group, using a combination of HUMARA assay and bisulfite-modified DNA sequencing, we found that the deletion affected the active chromosome X only in two cases (4%). Sequence analyses detected an inactivating somatic mutation of WTX in a single tumor, in which a strongly reduced expression of the mutant allele respect to the wild-type allele was observed, a finding not consistent with its localization on the active chromosome X. Overall, a functional somatic nullizygosity of the WTX gene was ascertained only in seven of the Wilms' tumors included in the study (approximately 7%). Our findings indicate that previously reported estimates on the proportion of Wilms' tumors due to WTX alterations should be reconsidered.

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Available from: Monica Terenziani, Apr 08, 2014
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    • "Activation of the IGF2 pathway through loss of heterozygosity (LOH) or loss of imprinting (LOI) has been identified in many of these cases, but it is unclear whether this is the initiating event in these cases (Hohenstein et al., 2015). WTX was identified as a Wilms' tumour gene on the X chromosome (Rivera et al., 2007), but the details of involvement of WTX loss in the origins of Wilms' tumours have been disputed (Perotti et al., 2008; Rivera et al., 2007; Wegert et al., 2009). In all, WT1 remains the best genetic and molecular entry point to study the origins of and mechanisms leading to Wilms' tumours. "
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    • "Somatic mutations and deletions of WTX have been reported in 6 to 30% of patients with Wilms tumors (WT), a kidney cancer typical of childhood, arising from multipotent mesenchymal kidney precursors [7,44,46,49]; WTX has later been identified as OS-CS disease-causing-gene, both in familial and sporadic cases. Despite germline mutations in tumor suppressor gene confer an elevated risk for cancer, and patients with WT and OS-CS share a similar distribution of WTX mutations, OS-CS is not associated with an increased neoplastic risk [51]. "
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    • "Recently in Wilms tumors, WTX (Wilms Tumor gene on the X-Chromosome) was discovered as another component of the β-CATENIN degradation complex where it directly interacts with β-CATENIN and APC [12,13]. Moreover, Wilms tumors are often characterized by a deregulated WNT-signaling pathway which can be attributed to mutations in the WTX-gene in 7 to 30% of all cases [14,15]. Due to its location on the X-chromosome, WTX resembles a one hit tumor suppressor which has therefore a higher penetrance in men than in women. "
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