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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    ABSTRACT: Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal to epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models to human tumour material of WT1-mutant and WT1 wild-type datasets identifies the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin. © 2015. Published by The Company of Biologists Ltd.
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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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    ABSTRACT: Osteopathia striata with cranial sclerosis (OS-CS) or Horan-Beighton syndrome is a rare X-linked dominant inherited bone dysplasia, characterized by longitudinal striations of long bones and cranial sclerosis. Patients can be asymptomatic or present with typical facial dysmorphism, sensory defects, internal organs anomalies, growth and mental retardation, depending on the severity of the disease. WTX gene (Xq11) has been recently identified as the disease causing gene. Aim of this article is to present the case of a 6 year old girl initially evaluated for bilateral hearing loss. Patient's head CT scan pointed out sclerosis of skull base and mastoid cells, and abnormal middle-ear ossification. Clinical examination of the patient and her mother were suspicious for OS-CS. The diagnosis was confirmed by X-rays examination showing typical longitudinal striation. Genetic analysis allowed the identification of maternally transmitted heterozygous nonsense c.1057C>T (p.R353X) WTX gene mutation. We also provide a systematic review of currently available knowledge about clinical, radiologic and genetic features typical of the OS-CS.
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    • "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). "
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    ABSTRACT: The WTX, Wilms tumor-associated tumor-suppressor gene, is present on the X chromosome and a single WTX mutation may be sufficient to promote carcinogenesis. Unlike the WT1 tumor suppressor, a transcription factor, WTX lacks conserved functional protein domains. To study the function of WTX, we constructed inducible cell lines expressing WTX and tumor-associated WTX mutants. Induction of WTX inhibited cell growth and caused G(1)/G(0) arrest. In contrast, a short, tumor-associated truncation mutant of WTX358 only slightly inhibited cell growth without a significant cell-cycle arrest, although expression of a longer truncation mutant WTX565 led to the growth inhibition and cell-cycle arrest to a similar extent as wild-type WTX. Like WT1, WTX slowed growth and caused cell-cycle arrest through p21 induction. Gene expression profiling showed that these two tumor-suppressors regulated genes in similar pathways, including those implicated in control of the cellular growth, cell cycle, cell death, cancer and cardiovascular system development. When gene expression changes mediated by wild-type WTX were compared with those affected by mutant forms, WTX565 showed a 55% overlap (228 genes) in differentially regulated genes, whereas WTX358 regulated only two genes affected by wild-type WTX, implying that amino-acid residues 358-561 are critical for WTX function.
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