Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Cancer volume 11, pages 111–121 (2011)Cite this article

Subjects

Key Points

  • WT1 and WTX seem to function as tumour suppressor genes (TSGs) in Wilms' tumours, but questions have arisen about these labels.

  • The lack of an increased frequency of Wilms' tumours or other malignancies in patients with osteopathia striata congenita with cranial sclerosis (OSCS) with WTX germline mutations initially challenged its designation as a TSG, but a recent observation of Wilms' tumour precursor lesions in a patient with OSCS supports this label.

  • In Wilms' tumours, WT1 conforms to a TSG label: patients heterozygous for WT1 germline mutations are predisposed to Wilms' tumour and WT1 is inactivated in tumours. These data link loss of WT1 function with enhanced cell viability and/or proliferation.

  • By contrast, ablation of WT1 at the initial stages of kidney development results in apoptosis and renal agenesis, indicating that it has a crucial role in maintaining cell viability.

  • In some leukaemias, the increased expression of WT1 compared with normal bone marrow cells, along with some reports of WT1 expression being a marker of poor prognosis, suggest that WT1 functions as an oncogene. By contrast, observations of WT1 inactivating mutations in leukaemias suggest it functions as a TSG.

  • WT1 has important roles in regulating normal differentiation in various organs and cell types. During both nephrogenesis and haematopoiesis, loss of WT1 or overexpression of WT1 is associated with differing phenotypic consequences, depending on the differentiation status of the cell.

  • The oncogenic or tumour suppressive effect of WT1 alteration is likely to be a result of how a cell at a particular stage of development responds to perturbations in normal differentiation. In short, either label may be misleading and/or inadequate when used to describe the function of WT1.

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?

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: WT1 mutations observed in Wilms' tumour and acute myeloid leukaemia (AML).
Figure 2: WTX mutations in Wilms' tumour and osteopathia striata congenita with cranial sclerosis (OSCS).
Figure 3: WT1 expression during kidney and myeloid differentiation, and phenotypic consequences of altered expression or gene ablation.

Similar content being viewed by others

References

  1. Bardeesy, N. et al. Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nature Genet. 7, 91–97 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Huff, V. Wilms tumor genetics. Am. J. Med. Genet. 79, 260–267 (1998). Although an older paper, this still provides a good basic summary of Wilms' tumour genetics along with primary data and an overall description of the type of WT1 mutations observed in patients with Wilms' tumour and their tumours that is still valid.

    Article  CAS  PubMed  Google Scholar 

  3. Koesters, R. et al. Mutational activation of the β-catenin proto-oncogene is a common event in the development of Wilms' tumors. Cancer Res. 59, 3880–3882 (1999).

    CAS  PubMed  Google Scholar 

  4. Rivera, M. N. et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 315, 642–645 (2007). This is the original report identifying WTX as a Wilms' tumour gene. It presents a nice story of going from observing a gene copy number change over a very short genomic region to identifying a new cancer-related gene.

    Article  CAS  PubMed  Google Scholar 

  5. Ruteshouser, E. C., Robinson, S. M. & Huff, V. Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third of tumors. Genes Chromosomes Cancer 47, 461–470 (2008). This paper presents data from more than 100 Wilms' tumours regarding the type, frequency and co-occurrence of WT1, WTX and CTNNB1 mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Perotti, D. et al. Functional inactivation of the WTX gene is not a frequent event in Wilms' tumors. Oncogene 27, 4625–4632 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Fukuzawa, R. et al. WTX mutations can occur both early and late in the pathogenesis of Wilms tumour. J. Med. Genet. 47, 791–794 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Miwa, H., Beran, M. & Saunders, G. F. Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 6, 405–409 (1992).

    CAS  PubMed  Google Scholar 

  9. Yamagami, T. et al. Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 87, 2878–2884 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Tsuboi, A. et al. Constitutive expression of the Wilms' tumor gene WT1 inhibits the differentiation of myeloid progenitor cells but promotes their proliferation in response to granulocyte-colony stimulating factor (G-CSF). Leuk. Res. 23, 499–505 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Ellisen, L. W., Carlesso, N., Cheng, T., Scadden, D. T. & Haber, D. A. The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. EMBO J. 20, 1897–1909 (2001). This early study assessed the effect of upregulation of WT1 in normal haematopoietic progenitor cells in addition to that in leukaemia cell lines. The discussion provides a thorough and balanced overview of the data on WT1 in leukaemia and haematopoiesis up to the time of the study.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Svedberg, H., Richter, J. & Gullberg, U. Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34+ progenitor cells. Leukemia 15, 1914–1922 (2001). This is a similar study to reference 11 on the effect of upregulation of WT1 in normal haematopoietic progenitor cells. A model on the variable phenotypic effects of WT1 expression during haematopoiesis is presented in the discussion.

    Article  CAS  PubMed  Google Scholar 

  13. Nishida, S. et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 107, 3303–3312 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Hosen, N. et al. The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis. Leukemia 21, 1783–1791 (2007). This is an excellent paper describing an extensive analysis of the temporal and spatial expression of Wt1 during mouse haematopoiesis and the role of Wt1 in leukaemogenesis using a Wt1 promoter-driven GFP reporter gene.

    Article  CAS  PubMed  Google Scholar 

  15. Inoue, K. et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 84, 3071–3079 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Bergmann, L. et al. High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 90, 1217–1225 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Trka, J. et al. Real-time quantitative PCR detection of WT1 gene expression in children with AML: prognostic significance, correlation with disease status and residual disease detection by flow cytometry. Leukemia 16, 1381–1389 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Garg, M., Moore, H., Tobal, K. & Liu Yin, J. A. Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia. Br. J. Haematol. 123, 49–59 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Oka, Y. et al. Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc. Natl Acad. Sci. USA 101, 13885–13890 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Keilholz, U. et al. A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood 113, 6541–6548 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Maslak, P. G. et al. Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T cell responses in patients with complete remission from acute myeloid leukemia. Blood 116, 171–179 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Breslow, N., Beckwith, J. B., Ciol, M. & Sharples, K. Age distribution of Wilms' tumor: report from the National Wilms' Tumor Study. Cancer Res. 48, 1653–1657 (1988).

    CAS  PubMed  Google Scholar 

  23. Knudson, A. G. & Strong, L. C. Mutation and cancer: a model for Wilms' tumor of the kidney. J. Natl Cancer Inst. 48, 313–324 (1972).

    PubMed  Google Scholar 

  24. Breslow, N. E., Beckwith, J. B., Perlman, E. J. & Reeve, A. E. Age distributions, birth weights, nephrogenic rests, and heterogeneity in the pathogenesis of Wilms tumor. Pediatr. Blood Cancer 47, 260–267 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Huff, V. et al. Evidence for genetic heterogeneity in familial Wilms' tumor. Cancer Res. 57, 1859–1862 (1997).

    CAS  PubMed  Google Scholar 

  26. Huff, V., Villalba, F., Strong, L. C. Saunders, G. F. Alteration of the WT1 gene in patients with Wilms' tumor and genitourinary anomalies. Am. J. Hum. Genet. 49, 44 (1991).

    Google Scholar 

  27. Major, M. B. et al. Wilms tumor suppressor WTX negatively regulates WNT/β-catenin signaling. Science 316, 1043–1046 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Rahman, N. et al. Evidence for a familial Wilms' tumour gene (FWT1) on chromosome 17q12-q21. Nature Genet. 13, 461–463 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. McDonald, J. M. et al. Linkage of familial Wilms' tumor predisposition to chromosome 19 and a two-locus model for the etiology of familial tumors. Cancer Res. 58, 1387–1390 (1998).

    CAS  PubMed  Google Scholar 

  30. Ogawa, O. et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour. Nature 362, 749–751 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Steenman, M. J. et al. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms' tumour. Nature Genet. 7, 433–439 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Wiedemann, H. Tumours and hemihypertrophy associated with Wiedemann-Beckwith syndrome. Eur. J. Pediatr. 141, 129 (1983).

    Article  Google Scholar 

  33. Weksberg, R., Shuman, C. & Smith, A. C. Beckwith-Wiedemann syndrome. Am. J. Med. Genet. C Semin. Med. Genet. 137C, 12–23 (2005).

    Article  PubMed  Google Scholar 

  34. Sparago, A. et al. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nature Genet. 36, 958–960 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Prawitt, D. et al. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor. Proc. Natl Acad. Sci. USA 102, 4085–4090 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rainier, S. et al. Relaxation of imprinted genes in human cancer. Nature 362, 747–749 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. Call, K. M. et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60, 509–520 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Gessler, M. et al. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343, 774–778 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Natoli, T. A. et al. A mammal-specific exon of WT1 is not required for development or fertility. Mol. Cell. Biol. 22, 4433–4438 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hammes, A. et al. Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106, 319–329 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Laity, J. H., Dyson, H. J. & Wright, P. E. Molecular basis for modulation of biological function by alternate splicing of the Wilms' tumor suppressor protein. Proc. Natl Acad. Sci. USA 97, 11932–11935 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Stoll, R. et al. Structure of the Wilms tumor suppressor protein zinc finger domain bound to DNA. J. Mol. Biol. 372, 1227–1245 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Larsson, S. H. et al. Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell 81, 391–401 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Miles, C. G. et al. Mice lacking the 68-amino-acid, mammal-specific N-terminal extension of WT1 develop normally and are fertile. Mol. Cell. Biol. 23, 2608–2613 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dallosso, A. R. et al. Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours. Hum. Mol. Genet. 13, 405–415 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Sharma, P. M., Bowman, M., Yu, B. F. & Sukumar, S. A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea. Proc. Natl Acad. Sci. USA 91, 9931–9935 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gunning, K. B., Cohn, S. L., Tomlinson, G. E., Strong, L. C. & Huff, V. Analysis of possible WT1 RNA processing in primary Wilms tumors. Oncogene 13, 1179–1185 (1996).

    CAS  PubMed  Google Scholar 

  48. Li, J. B. et al. Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324, 1210–1213 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Ye, Y., Raychaudhuri, B., Gurney, A., Campbell, C. E. & Williams, B. R. Regulation of WT1 by phosphorylation: inhibition of DNA binding, alteration of transcriptional activity and cellular translocation. EMBO J. 15, 5606–5615 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smolen, G. A., Vassileva, M. T., Wells, J., Matunis, M. J. & Haber, D. A. SUMO-1 modification of the Wilms' tumor suppressor WT1. Cancer Res. 64, 7846–7851 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Makki, M. S., Heinzel, T. & Englert, C. TSA downregulates Wilms tumor gene 1 (Wt1) expression at multiple levels. Nucleic Acids Res. 36, 4067–4078 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gao, F. et al. The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis. Proc. Natl Acad. Sci. USA 103, 11987–11992 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Martinez-Estrada, O. M. et al. Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin. Nature Genet. 42, 89–93 (2010). This is an excellent paper describing the role of WT1 in epithelial to mesenchymal transition in cardiovascular progenitors cells through its regulation of two genes crucial for this process.

    Article  CAS  PubMed  Google Scholar 

  54. Pritchard-Jones, K. et al. The candidate Wilms' tumour gene is involved in genitourinary development. Nature 346, 194–197 (1990).

    Article  CAS  PubMed  Google Scholar 

  55. Buckler, A. J., Pelletier, J., Haber, D. A., Glaser, T. & Housman, D. E. Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development. Mol. Cell. Biol. 11, 1707–1712 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kreidberg, J. A. et al. WT-1 is required for early kidney development. Cell 74, 679–691 (1993). This paper describes the phenotype effect of germline ablation of Wt1 in the mouse and demonstrates that Wt1 is crucial for the normal development of many organ systems, including the kidney and gonads (as would be predicted by the phenotypes exhibited by patients carrying germline WT1 mutations).

    Article  CAS  PubMed  Google Scholar 

  57. Hu, Q. et al. Wt1 ablation and Igf2-upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation. J. Clin. Invest. 1 Dec 2010 (doi: 10.1172/JCI43772). This paper describes the first mouse model for Wilms' tumour, which demonstrates that mosaic somatic Wt1 ablation in conjunction with Igf2 biallelic expression is sufficient for Wilms' tumours. Additionally, complete somatic ablation of Wt1 results in a complete block in kidney development.

    Article  CAS  Google Scholar 

  58. Davies, J. A. et al. Development of an siRNA-based method for repressing specific genes in renal organ culture and its use to show that the Wt1 tumour suppressor is required for nephron differentiation. Hum. Mol. Genet. 13, 235–246 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Pelletier, J. et al. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67, 437–447 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Huff, V. Genotype/phenotype correlations in Wilms' tumor. Med. Pediatr. Oncol. 27, 408–414 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Royer-Pokora, B. et al. Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am. J. Med. Genet. A 127, 249–257 (2004).

    Article  Google Scholar 

  62. Koziell, A. et al. Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy? Clin. Endocrinol. 52, 519–524 (2000).

    Article  CAS  Google Scholar 

  63. Barbaux, S. et al. Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nature Genet. 17, 467–470 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Baird, P. N. & Simmons, P. J. Expression of the Wilms' tumor gene (WT1) in normal hemopoiesis. Exp. Hematol. 25, 312–320 (1997).

    CAS  PubMed  Google Scholar 

  65. Maurer, U., Weidmann, E., Karakas, T., Hoelzer, D. & Bergmann, L. Wilms tumor gene (wt1) mRNA is equally expressed in blast cells from acute myeloid leukemia and normal CD34+ progenitors. Blood 90, 4230–4232 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Hosen, N. et al. Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells. Br. J. Haematol. 116, 409–420 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Alberta, J. A. et al. Role of the WT1 tumor suppressor in murine hematopoiesis. Blood 101, 2570–2574 (2003). This was the first study to examine the role of Wt1 in haematopoiesis in vivo . Creating chimaeras of Wt1 -wild-type and Wt1 -null cells, this work established that Wt1 is not required for normal haematopoiesis, but is important for robust haematopoiesis.

    Article  CAS  PubMed  Google Scholar 

  68. Pritchard-Jones, K., Renshaw, J. & King-Underwood, L. The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient. Hum. Mol. Genet. 3, 1633–1637 (1994).

    Article  CAS  PubMed  Google Scholar 

  69. Menssen, H. D. et al. Presence of Wilms' tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia 9, 1060–1067 (1995).

    CAS  PubMed  Google Scholar 

  70. Inoue, K. et al. Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood 88, 2267–2278 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Gaiger, A. et al. Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia 12, 1886–1894 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Yanada, M. et al. Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia. Leuk. Lymphoma 45, 1803–1808 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Rodrigues, P. C. et al. Prognostic significance of WT1 gene expression in pediatric acute myeloid leukemia. Pediatr. Blood Cancer 49, 133–138 (2007).

    Article  PubMed  Google Scholar 

  74. Bansal, H. et al. Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias. Blood 116, 4591–4599 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Summers, K. et al. Wilms' tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 21, 550–551; author reply 552 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Paschka, P. et al. Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J. Clin. Oncol. 26, 4595–4602 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hollink, I. H. et al. Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood 113, 5951–5960 (2009). This study of a large panel of paediatric AMLs not only confirmed earlier reports of WT1 mutations being an independent indicator of poor prognosis, but it also provided novel data regarding the association of WT1 mutations with other genetic alterations and an assessment of WT1 mutation status in paired samples taken at diagnosis and relapse.

    Article  CAS  PubMed  Google Scholar 

  78. Virappane, P. et al. Mutation of the Wilms' tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J. Clin. Oncol. 26, 5429–5435 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Dobbin, E. et al. Tel/PDGFRβeta induces stem cell differentiation via the Ras/ERK and STAT5 signaling pathways. Exp. Hematol. 37, 111–121 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Luo, X. N. et al. The tumor suppressor gene WT1 inhibits ras-mediated transformation. Oncogene 11, 743–750 (1995).

    CAS  PubMed  Google Scholar 

  81. Vicent, S. et al. Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models. J. Clin. Invest. 120, 3940–3952 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gross, I. et al. The receptor tyrosine kinase regulator Sprouty1 is a target of the tumor suppressor WT1 and important for kidney development. J. Biol. Chem. 278, 41420–41430 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Morrison, D. J., Kim, M. K., Berkofsky-Fessler, W. & Licht, J. D. WT1 induction of mitogen-activated protein kinase phosphatase 3 represents a novel mechanism of growth suppression. Mol. Cancer Res. 6, 1225–1231 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Grohmann, A., Tanneberger, K., Alzner, A., Schneikert, J. & Behrens, J. AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane. J. Cell Sci. 120, 3738–3747 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Jenkins, Z. A. et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nature Genet. 41, 95–100 (2009). This paper was the first to describe the phenotypic consequence of germline WTX mutations.

    Article  CAS  PubMed  Google Scholar 

  86. Rivera, M. N. et al. The tumor suppressor WTX shuttles to the nucleus and modulates WT1 activity. Proc. Natl Acad. Sci. USA 106, 8338–8343 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Fukuzawa, R., Anaka, M. R., Weeks, R. J., Morison, I. M. & Reeve, A. E. Canonical WNT signalling determines lineage specificity in Wilms tumour. Oncogene 28, 1063–1075 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Wegert, J. et al. WTX inactivation is a frequent, but late event in Wilms tumors without apparent clinical impact. Genes Chromosomes Cancer 48, 1102–1111 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Park, S. et al. Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour. Nature Genet. 5, 363–367 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Maiti, S., Alam, R., Amos, C. I. & Huff, V. Frequent association of β-catenin and WT1 mutations in Wilms tumors. Cancer Res. 60, 6288–6292 (2000).

    CAS  PubMed  Google Scholar 

  91. Fukuzawa, R. et al. Myogenesis in Wilms' tumors is associated with mutations of the WT1 gene and activation of Bcl-2 and the Wnt signaling pathway. Pediatr. Dev. Pathol. 7, 125–137 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Satoh, Y. et al. Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours. Br. J. Cancer 95, 541–547 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fukuzawa, R. et al. Wilms tumour histology is determined by distinct types of precursor lesions and not epigenetic changes. J. Pathol. 215, 377–387 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Haruta, M. et al. Duplication of paternal IGF2 or loss of maternal IGF2 imprinting occurs in half of Wilms tumors with various structural WT1 abnormalities. Genes Chromosomes Cancer 47, 712–727 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Royer-Pokora, B. et al. Clinical relevance of mutations in the Wilms tumor suppressor 1 gene WT1 and the cadherin-associated protein β1 gene CTNNB1 for patients with Wilms tumors: results of long-term surveillance of 71 patients from International Society of Pediatric Oncology Study 9/Society for Pediatric Oncology. Cancer 113, 1080–1089 (2008).

    Article  PubMed  Google Scholar 

  96. Corbin, M. et al. WNT/β-catenin pathway activation in Wilms tumors: a unifying mechanism with multiple entries? Genes Chromosomes Cancer 48, 816–827 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Fukuzawa, R., Heathcott, R. W., More, H. E. & Reeve, A. E. Sequential WT1 and CTNNB1 mutations and alterations of β-catenin localization in intralobar nephrogenic rests and associated Wilms tumours: two case studies. J. Clin. Pathol. 60, 1013–1016 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Inoue, K. et al. Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 89, 1405–1412 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Daugherty, R. L. & Gottardi, C. J. Phospho-regulation of β-catenin adhesion and signaling functions. Physiology 22, 303–309 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. MacDonald, B. T., Tamai, K. & He, X. Wnt/β-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9–26 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Heuberger, J. & Birchmeier, W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb. Perspect. Biol. 2, a002915 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Iglesias, D. M. et al. Canonical WNT signaling during kidney development. Am. J. Physiol. Renal Physiol. 293, F494–F500 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Saadi-Kheddouci, S. et al. Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the β-catenin gene. Oncogene 20, 5972–5981 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Kuure, S., Popsueva, A., Jakobson, M., Sainio, K. & Sariola, H. Glycogen synthase kinase-3 inactivation and stabilization of β-catenin induce nephron differentiation in isolated mouse and rat kidney mesenchymes. J. Am. Soc. Nephrol. 18, 1130–1139 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Park, J. S., Valerius, M. T. & McMahon, A. P. Wnt/β-catenin signaling regulates nephron induction during mouse kidney development. Development 134, 2533–2539 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Vainio, S. & Lin, Y. Coordinating early kidney development: lessons from gene targeting. Nature Rev. Genet. 3, 533–543 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Beckwith, J. B. in Renal Pathology with Clinical and Functional Correlations (eds C. C. Tisher & Brenner, B. M.) (J. B. Lippincott Company, Philadelphia, 1994). This presents an excellent description of the histology of Wilms' tumours, along with a model regarding the ontogenic relationship between histologically different Wilms' tumours and other kidney tumours.

    Google Scholar 

  108. Kaneda, A. et al. Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc. Natl Acad. Sci. USA 104, 20926–20931 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bove, K. E., Lewis, C. & Debrosse, B. K. Proliferation and maturation indices in nephrogenic rests and Wilms tumor; the emergence of heterogeneity from dormant nodular renal blastema. Pediatr. Pathol. Lab. Med. 15, 223–244 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Miwa, H. et al. RNA expression of the WT1 gene in Wilms' tumors in relation to histology. J. Natl Cancer Inst 84, 181–187 (1992).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author would like to thank C. Ruteshouser for her assistance. The author's work is supported by US NIH grants CA34936 and DK069599, NCI CCSG grant CA16672 and CPRIT grants RP100329 and RP110234.

Author information

Authors and Affiliations

  1. Department of Genetics, Unit 1010, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Vicki Huff

  2. Graduate programs in Genes and Development and Human Molecular Genetics, UT-Houston Graduate School of Biomedical Sciences, Houston, 77025, Texas, USA

    Vicki Huff

Authors
  1. Vicki Huff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vicki Huff.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Glossary

Autosomal dominant trait

A trait that is the result of being heterozygous for an allele for a gene that is present on any non-sex (not the X or Y) chromosome.

Aniridia

Lack of development of the iris of the eye.

Rhabdomyosarcoma

A tumour of skeletal muscle.

Intermediate mesoderm

Region of the embryonic mesoderm from which the kidneys and gonads arise.

Metanephric blastema

A subpopulation of the intermediate mesoderm that induces the outgrowth of the ureteric bud and from which the nephrons and stroma of the mature kidney arise.

Renal agenesis

Lack of development of the kidney.

Kidney rudiment explant culture

Embryonic kidneys as early as the stage at which the ureteric bud begins to invade the metanephric mesenchyme can be grown in culture chambers on filters. The reciprocal inductive interactions between the ureteric bud and the metanephric mesenchyme occur in culture, resulting in a three-dimensional structure of nephrons and collecting ducts like a normal kidney but without capillary invasion.

Ureteric bud

A developmental structure that buds off the mesonephric (Wolffian) duct, invades the metanephric mesenchyme and develops into the collecting duct system of the kidney.

Glomerulosclerosis

A general term to describe scarring of the glomerulus, the primary filtration structure in the kidney predominantly composed of capillaries and podocytes.

Denys–Drash syndrome

A phenotypic triad of Wilms' tumour, congenital genitourinary anomalies and early-onset renal failure.

Gonadoblastoma

A tumour arising in the developing ovary or testes.

TEL–PDGFBR and AML1–ETO

Two different fusion proteins resulting from chromosomal translocations and observed in some myeloid leukaemias. In TEL–PDGFBR the N-terminal region of TEL is fused with the domain of transmembrane and cytoplasmic domains of the receptor kinase protein, PDGFBR. In AML1–ETO the DNA binding domain of AML1 is fused with the ETO co-repressor protein.

Comma-shaped and S-shaped bodies

Two morphological stages observed as induced metanephric mesenchyme differentiates and epithelializes to form mature nephrons.

Osteopathia striata congenita with cranial sclerosis

(OSCS). X-linked dominant condition in which increased bone density and aberrant development of the skull is commonly observed. Fetal or perinatal lethality is often observed in males.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huff, V. Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. Nat Rev Cancer 11, 111–121 (2011). https://doi.org/10.1038/nrc3002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3002

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer