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

Abstract

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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Acknowledgements

We thank all the clinicians, pathologists, surgeons and the Italian institutions that contributed biological samples of patients enrolled in the AIEOP 2003 WT trial, and in particular: Paolo Pierani, Azienda Ospedaliera G Salesi, Ancona; Nicola Santoro and Gianpaolo Ariamone, Azienda Ospedaliera Policlinico Consorziale, Bari; Pieremilio Cornelli, Provenzi Massimo, and Daniela Chinaglia, Ospedali Riuniti di Bergamo; Fraia Melchionda and Nunzio Salfi, Azienda Ospedaliera S Orsola Malpighi, Bologna; Luca Tonegatti and Katia Tettoni, Spedali Civili, Brescia; Andrea Di Cataldo, Centro di Riferimento Regionale di Ematologia ed Oncologia Pediatrica, Catania; Eulalia Galea, Azienda Ospedaliera Pugliese Ciaccio, Catanzaro; Domenico Sperlì, Azienda Ospedaliera dell’ Annunziata, Cosenza; Maria Elena Michelini, Azienda Ospedaliera Universitaria di Ferrara; Angela Tamburini, Azienda Ospedaliera A Meyer, Firenze; Angela Rita Sementa and Claudio Gambini, Istituto G Gaslini, Genova; Monica Cellini, Azienda Ospedaliera di Modena; Paolo Indolfi and Vittoria Donofrio, Seconda Università degli Studi di Napoli, Azienda Universitaria Policlinico, Napoli; Monica Leutner, Azienda Ospedaliera ‘Maggiore della carità’, Novara; Paolo D’Angelo, Ospedale dei bambini, Palermo; Giancarlo Izzi and Angelica Barone, Azienda Ospedaliera di Parma; Nicola Pappalepore and Giulia Sindici, Ospedale Civile di Pescara; Claudio Favre and Gabriella Casazza, Ospedale S Chiara, Pisa; Roberta Pericoli, Ospedale Infermi, Rimini; Lucia Miglionico, Casa Sollievo della Sofferenza, S Giovanni Rotondo; Angela Pucci, Maurizio Bianchi, and Marco Forni, Azienda Ospedaliera materno-infantile OIRM S Anna, Torino; Paolo Tamaro, Azienda Ospedaliera Burlo Garofolo, Trieste; Silvana Binda, Ospedale F del Ponte, Varese. We also thank Monica Miozzo, Department of Medicine, Surgery and Dentistry, University of Milan, for providing the reagents and conditions to perform HUMARA assays; Donata Penso, Davide Conte and Fernando Ravagnani of INT for expert assistance in sequencing analysis, for advice in qPCR experiments, and for providing samples of blood donors, respectively.

This work was supported by grants from the Associazione Bianca Garavaglia, Busto Arsizio, Varese and the Italian Association for Cancer Research (AIRC).

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Perotti, D., Gamba, B., Sardella, M. et al. Functional inactivation of the WTX gene is not a frequent event in Wilms’ tumors. Oncogene 27, 4625–4632 (2008). https://doi.org/10.1038/onc.2008.93

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