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The genetic changes of Wilms tumour

Nature Reviews Nephrology (2019) | Download Citation


Wilms tumour is the most common renal malignancy of childhood. The disease is curable in the majority of cases, albeit at considerable cost in terms of late treatment-related effects in some children. However, one in ten children with Wilms tumour will die of their disease despite modern treatment approaches. The genetic changes that underpin Wilms tumour have been defined by studies of familial cases and by unbiased DNA sequencing of tumour genomes. Together, these approaches have defined the landscape of cancer genes that are operative in Wilms tumour, many of which are intricately linked to the control of fetal nephrogenesis. Advances in our understanding of the germline and somatic genetic changes that underlie Wilms tumour may translate into better patient outcomes. Improvements in risk stratification have already been seen through the introduction of molecular biomarkers into clinical practice. A host of additional biomarkers are due to undergo clinical validation. Identifying actionable mutations has led to potential new targets, with some novel compounds undergoing testing in early phase trials. Avenues that warrant further exploration include targeting Wilms tumour cancer genes with a non-redundant role in nephrogenesis and targeting the fetal renal transcriptome.

Key points

  • Wilms tumour is the most common childhood renal malignancy; the incidence differs between ethnicities worldwide.

  • The treatment of Wilms tumour can be considered a success story, but the management of patients with high-risk histology, bilateral tumours and/or relapsed disease remains challenging.

  • The genetic changes that underpin Wilms tumour are diverse and involve ~40 cancer genes; this diversity is particularly surprising given the monotonous driver landscape of other childhood renal tumours.

  • Genome sequencing of Wilms tumours has identified cancer genes that harbour likely driver mutations, including epigenetic remodellers, microRNA processing genes and the transcription factors SIX1 and SIX2.

  • Many Wilms tumour-related genes have pivotal roles in the developing kidney, supporting the hypothesis that Wilms tumour development is coupled to aberrant nephrogenesis.

  • Targeting somatic variants with prognostic significance, as well as the fetal renal transcriptome, may provide promising therapeutic avenues for patients with relapsed or refractory disease.

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  1. 1.

    Breslow, N., Olshan, A., Beckwith, J. B. & Green, D. M. Epidemiology of Wilms tumor. Med. Pediatr. Oncol. 21, 172–181 (1993).

  2. 2.

    Rivera, M. N. & Haber, D. A. Wilms’ tumour: connecting tumorigenesis and organ development in the kidney. Nat. Rev. Cancer 5, 699–712 (2005).

  3. 3.

    Ma, X. et al. Pan-cancer genome and transcriptome analyses of 1,699 paediatric leukaemias and solid tumours. Nature 555, 371–376 (2018).

  4. 4.

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

  5. 5.

    Maschietto, M. et al. The IGF signalling pathway in Wilms tumours—a report from the ENCCA renal tumours biology-driven drug development workshop. Oncotarget 5, 8014–8026 (2014).

  6. 6.

    Lee, S. B. & Haber, D. A. Wilms Tumor and the WT1 gene. Exp. Cell Res. 264, 74–99 (2001).

  7. 7.

    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).

  8. 8.

    Torrezan, G. T. et al. Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour. Nat. Commun. 5, 4039 (2014).

  9. 9.

    Rakheja, D. et al. Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat. Commun. 2, 4802 (2014).

  10. 10.

    Walz, A. L. et al. Recurrent DGCR8, DROSHA, and SIX homeodomain mutations in favorable histology Wilms tumors. Cancer Cell 27, 286–297 (2015).

  11. 11.

    Wegert, J. et al. Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors. Cancer Cell 27, 298–311 (2015).

  12. 12.

    Gadd, S. et al. A Children’s Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. Nat. Genet. 49, 1487–1494 (2017).

  13. 13.

    Breslow, N., Beck, J. B., Gol, M. & Sharpies, K. Age distribution of Wilms’ tumor: report from the National Wilms’ Tumor Study. Cancer Res. 48, 1653–1657 (1988).

  14. 14.

    Scott, R. H., Stiller, C. A., Walker, L. & Rahman, N. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J. Med. Genet. 43, 705–715 (2006).

  15. 15.

    Maas, S. M. et al. Phenotype, cancer risk, and surveillance in Beckwith–Wiedemann syndrome depending on molecular genetic subgroups. Am. J. Med. Genet. A 170, 2248–2260 (2016).

  16. 16.

    Nakata, K. et al. Childhood cancer incidence and survival in Japan and England: a population-based study (1993–2010). Cancer Sci. 109, 422–434 (2018).

  17. 17.

    Heck, J. E. et al. Risk of childhood cancer by maternal birthplace. JAMA Pediatr. 170, 585 (2016).

  18. 18.

    Howe, H. L. et al. Annual report to the nation on the status of cancer, 1975–2003, featuring cancer among U. S. Hispanic/Latino populations. Cancer 107, 1711–1742 (2006).

  19. 19.

    Jia, W. et al. Association between HACE1 gene polymorphisms and Wilms’ tumor risk in a Chinese population. Cancer Invest. 35, 633–638 (2017).

  20. 20.

    Fu, W. et al. BARD1 gene polymorphisms confer nephroblastoma susceptibility. EBioMedicine 16, 101–105 (2017).

  21. 21.

    Turnbull, C. et al. A genome-wide association study identifies susceptibility loci for Wilms tumor. Nat. Genet. 44, 681–684 (2012).

  22. 22.

    Fukuzawa, R. et al. Epigenetic differences between Wilms’ tumours in white and east-Asian children. Lancet 363, 446–451 (2004).

  23. 23.

    Kaneko, Y. et al. A high incidence of WT1 abnormality in bilateral Wilms tumours in Japan and the penetrance rates in children with WT1 germline mutation. Br. J. Cancer 112, 1121–1133 (2015).

  24. 24.

    Oue, T. et al. Anaplastic histology Wilms’ tumors registered to the Japan Wilms’ Tumor Study Group are less aggressive than that in the National Wilms’ Tumor Study 5. Pediatr. Surg. Int. 32, 851–855 (2016).

  25. 25.

    van den Heuvel-Eibrink, M. M. et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP–RTSG 2016 protocol. Nat. Rev. Urol. 14, 743–752 (2017).

  26. 26.

    Metzger, M. L. & Dome, J. S. Current therapy for Wilms’ tumor. Oncologist 10, 815–826 (2005).

  27. 27.

    Brok, J., Treger, T. D., Gooskens, S. L., van den Heuvel-Eibrink, M. M. & Pritchard-Jones, K. Biology and treatment of renal tumours in childhood. Eur. J. Cancer 68, 179–195 (2016).

  28. 28.

    Dome, J. S. et al. Advances in Wilms tumor treatment and biology: progress through international collaboration. J. Clin. Oncol. 33, 2999–3007 (2015).

  29. 29.

    Dome, J. S., Perlman, E. J. & Graf, N. Risk stratification for wilms tumor: current approach and future directions. Am. Soc. Clin. Oncol. Educ. Book (2014).

  30. 30.

    Krepischi, A. C. V. et al. Genomic imbalances pinpoint potential oncogenes and tumor suppressors in Wilms tumors. Mol. Cytogenet. 9, 20 (2016).

  31. 31.

    Grundy, P. E. et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J. Clin. Oncol. 23, 7312–7321 (2005).

  32. 32.

    Fernandez, C. V. et al. Clinical outcome and biological predictors of relapse after nephrectomy only for very low-risk Wilms tumor. Ann. Surg. 265, 835–840 (2017).

  33. 33.

    Perlman, E. J. et al. WT1 mutation and 11P15 loss of heterozygosity predict relapse in very low-risk wilms tumors treated with surgery alone: a children’s oncology group study. J. Clin. Oncol. 29, 698–703 (2011).

  34. 34.

    Karlsson, J. et al. Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer. Nat. Genet. 50, 944–950 (2018).

  35. 35.

    Pritchard-Jones, K. et al. Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms’ tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial. Lancet 386, 1156–1164 (2015).

  36. 36.

    Gramatges, M. M. & Bhatia, S. Evidence for genetic risk contributing to long-term adverse treatment effects in childhood cancer survivors. Annu. Rev. Med. 69, 247–262 (2018).

  37. 37.

    Spreafico, F. et al. Treatment of relapsed Wilms tumors: lessons learned. Expert Rev. Anticancer Ther. 9, 1807–1815 (2009).

  38. 38.

    Brok, J. et al. Relapse of Wilms’ tumour and detection methods: a retrospective analysis of the 2001 Renal Tumour Study Group–International Society of Paediatric Oncology Wilms’ tumour protocol database. Lancet Oncol. 19, P1072–P1081 (2018).

  39. 39.

    Ha, T. C. et al. An international strategy to determine the role of high dose therapy in recurrent Wilms’ tumour. Eur. J. Cancer 49, 194–210 (2013).

  40. 40.

    Furtwängler, R. et al. Update on relapses in unilateral nephroblastoma registered in 3 consecutive SIOP/GPOH studies - a report from the GPOH-nephroblastoma study group. Klin. Padiatr. 223, 113–119 (2011).

  41. 41.

    Malogolowkin, M. et al. Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor Study Group. Pediatr. Blood Cancer 50, 236–241 (2008).

  42. 42.

    Green, D. M. et al. Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group. Pediatr. Blood Cancer 48, 493–499 (2007).

  43. 43.

    Green, D. M. et al. Treatment with nephrectomy only for small, stage I/favorable histology Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J. Clin. Oncol. 19, 3719–3724 (2001).

  44. 44.

    Chagtai, T. et al. Gain of 1q as a prognostic biomarker in Wilms tumors (WTs) treated with preoperative chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 trial: a SIOP Renal Tumours Biology Consortium Study. J. Clin. Oncol. 34, 3195–3203 (2016).

  45. 45.

    Gratias, E. J. et al. Association of chromosome 1q gain with inferior survival in favorable-histology Wilms tumor: a report from the Children’s Oncology Group. J. Clin. Oncol. 34, 3189–3194 (2016).

  46. 46.

    Segers, H. et al. Gain of 1q is a marker of poor prognosis in Wilms’ tumors. Genes Chromosomes Cancer 52, 1065–1074 (2013).

  47. 47.

    Stiller, C. A. & Olshan, A. F. in Renal Tumors of Childhood - Biology and Therapy (eds Prithcard-Jones, K. & Dome, J.) 1–17 (Springer, 2016).

  48. 48.

    Charlton, J. et al. Comparative methylome analysis identifies new tumour subtypes and biomarkers for transformation of nephrogenic rests into Wilms tumour. Genome Med. 7, 11 (2015).

  49. 49.

    Charlton, J., Irtan, S., Bergeron, C. & Pritchard-Jones, K. Bilateral Wilms tumour: a review of clinical and molecular features. Expert Rev. Mol. Med. 19, e8 (2017).

  50. 50.

    Dome, J. S. et al. Treatment of anaplastic histology Wilms’ tumor: results from the fifth National Wilms’ Tumor Study. J. Clin. Oncol. 24, 2352–2358 (2006).

  51. 51.

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

  52. 52.

    Maschietto, M. et al. TP53 mutational status is a potential marker for risk stratification in Wilms tumour with diffuse anaplasia. PLOS ONE 9, e109924 (2014).

  53. 53.

    Ooms, A. H. A. G. et al. Significance of TP53 mutation in Wilms tumors with diffuse anaplasia: a report from the Children’s Oncology Group. Clin. Cancer Res. 22, 5582–5591 (2016).

  54. 54.

    Wegert, J. et al. TP53 alterations in Wilms tumour represent progression events with strong intratumour heterogeneity that are closely linked but not limited to anaplasia. J. Pathol. Clin. Res. 3, 234–248 (2017).

  55. 55.

    Treger, T. D. et al. Somatic TP53 mutations are detectable in circulating tumor DNA from children with anaplastic Wilms tumors. Transl Oncol. 11, 1301–1306 (2018).

  56. 56.

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

  57. 57.

    Hohenstein, P., Pritchard-Jones, K. & Charlton, J. The yin and yang of kidney development and Wilms’ tumors. Genes Dev. 29, 467–482 (2015).

  58. 58.

    Trink, A. et al. Geometry of gene expression space of Wilms’ tumors from human patients. Neoplasia 20, 871–881 (2018).

  59. 59.

    Dekel, B. et al. Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney. Cancer Res. 66, 6040–6049 (2006).

  60. 60.

    Metsuyanim, S. et al. Accumulation of malignant renal stem cells is associated with epigenetic changes in normal renal progenitor genes. Stem Cells 26, 1808–1817 (2008).

  61. 61.

    Pode-Shakked, N. et al. Evidence of in vitro preservation of human nephrogenesis at the single-cell level. Stem Cell Rep. 9, 279–291 (2017).

  62. 62.

    Gadd, S. et al. Clinically relevant subsets identified by gene expression patterns support a revised ontogenic model of Wilms tumor: a Children’s Oncology Group Study. Neoplasia 14, 742–756 (2012).

  63. 63.

    Pode-Shakked, N. et al. Dissecting stages of human kidney development and tumorigenesis with surface markers affords simple prospective purification of nephron stem cells. Sci. Rep. 6, 23562 (2016).

  64. 64.

    Pode-Shakked, N. et al. The isolation and characterization of renal cancer initiating cells from human Wilms’ tumour xenografts unveils new therapeutic targets. EMBO Mol. Med. 5, 18–37 (2013).

  65. 65.

    Shukrun, R. et al. Wilms’ tumor blastemal stem cells dedifferentiate to propagate the tumor bulk. Stem Cell Rep. 3, 24–33 (2014).

  66. 66.

    Perdigão-Henriques, R. et al. miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1 transcriptional repressor complexes. Oncogene 35, 158–172 (2016).

  67. 67.

    Polosukhina, D. et al. Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors. Mol. Oncol. 11, 405–421 (2017).

  68. 68.

    Young, M. D. et al. Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science 361, 594–599 (2018).

  69. 69.

    Merks, J. H. M., Caron, H. N. & Hennekam, R. C. M. High incidence of malformation syndromes in a series of 1,073 children with cancer. Am. J. Med. Genet. A 134A, 132–143 (2005).

  70. 70.

    Dumoucel, S. et al. Malformations, genetic abnormalities, and Wilms tumor. Pediatr. Blood Cancer 61, 140–144 (2014).

  71. 71.

    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).

  72. 72.

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

  73. 73.

    Pelletier, J. et al. WT1 mutations contribute to abnormal genital system development and hereditary Wilms’ tumour. Nature 353, 431–434 (1991).

  74. 74.

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

  75. 75.

    Kreidberg, J. A. et al. WT-1 is required for early kidney development. Cell 74, 679–691 (1993).

  76. 76.

    Hu, Q. et al. Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation. J. Clin. Invest. 121, 174–183 (2011).

  77. 77.

    Hartwig, S. et al. Genomic characterization of Wilms’ tumor suppressor 1 targets in nephron progenitor cells during kidney development. Development 137, 1189–1203 (2010).

  78. 78.

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

  79. 79.

    Clericuzio, C., Hingorani, M., Crolla, J. A., van Heyningen, V. & Verloes, A. Clinical utility gene card for: WAGR syndrome. Eur. J. Hum. Genet. 19, 492 (2011).

  80. 80.

    Breslow, N. E. et al. Characteristics and outcomes of children with the Wilms tumor-Aniridia syndrome: a report from the National Wilms Tumor Study Group. J. Clin. Oncol. 21, 4579–4585 (2003).

  81. 81.

    Mueller, R. F. The Denys-Drash syndrome. J. Med. Genet. 31, 471–477 (1994).

  82. 82.

    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).

  83. 83.

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

  84. 84.

    Karnik, P., Chen, P., Paris, M., Yeger, H. & Williams, B. R. Loss of heterozygosity at chromosome 11p15 in Wilms tumors: identification of two independent regions. Oncogene 17, 237–240 (1998).

  85. 85.

    Cresswell, G. D. et al. Intra-tumor genetic heterogeneity in Wilms tumor: clonal evolution and clinical implications. EBioMedicine 0, 991–1000 (2016).

  86. 86.

    Charles, A. K., Brown, K. W. & Berry, P. J. Microdissecting the genetic events in nephrogenic rests and Wilms’ tumor development. Am. J. Pathol. 153, 991–1000 (1998).

  87. 87.

    Mussa, A. et al. Cancer risk in Beckwith-Wiedemann syndrome: a systematic review and meta-analysis outlining a novel (Epi)genotype specific histotype targeted screening protocol. J. Pediatr. 176, 142–149 (2016).

  88. 88.

    Cooper, W. N. et al. Molecular subtypes and phenotypic expression of Beckwith–Wiedemann syndrome. Eur. J. Hum. Genet. 13, 1025–1032 (2005).

  89. 89.

    Scott, R. H. et al. Stratification of Wilms tumor by genetic and epigenetic analysis. Oncotarget 3, 327–335 (2012).

  90. 90.

    Pilia, G. et al. Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome. Nat. Genet. 12, 241–247 (1996).

  91. 91.

    Astuti, D. et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat. Genet. 44, 277–284 (2012).

  92. 92.

    Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

  93. 93.

    Ruteshouser, E. C. & Huff, V. Familial Wilms tumor. Am. J. Med. Genet. 129C, 29–34 (2004).

  94. 94.

    Palculict, T. B. et al. Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour. J. Med. Genet. 53, 385–388 (2016).

  95. 95.

    Hanks, S. et al. Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour. Nat. Commun. 5, 4398 (2014).

  96. 96.

    Martins, A. G., Pinto, A. T., Domingues, R. & Cavaco, B. M. Identification of a novel CTR9 germline mutation in a family with Wilms tumor. Eur. J. Med. Genet. 61, 294–299 (2018).

  97. 97.

    Van Oss, S. B., Cucinotta, C. E. & Arndt, K. M. Emerging insights into the roles of the Paf1 complex in gene regulation. Trends Biochem. Sci. 42, 788–798 (2017).

  98. 98.

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

  99. 99.

    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).

  100. 100.

    Halliday, B. J. et al. Germline mutations and somatic inactivation of TRIM28 in Wilms tumour. PLOS Genet. 14, e1007399 (2018).

  101. 101.

    Dihazi, G. H. et al. Proteomic analysis of embryonic kidney development: Heterochromatin proteins as epigenetic regulators of nephrogenesis. Sci. Rep. 5, 13951 (2015).

  102. 102.

    Mahamdallie, S. S. et al. Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat. Genet. 47, 1471–1474 (2015).

  103. 103.

    Cole, B. L., Pritchard, C. C., Anderson, M. & Leary, S. E. Targeted sequencing of malignant supratentorial pediatric brain tumors demonstrates a high frequency of clinically relevant mutations. Pediatr. Dev. Pathol. 21, 380–388 (2017).

  104. 104.

    Southey, M. C. et al. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. J. Med. Genet. 53, 800–811 (2016).

  105. 105.

    Carlo, M. I. et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 4, 1228–1235 (2018).

  106. 106.

    Gopalakrishnan, V. REST and the RESTless: in stem cells and beyond. Future Neurol. 4, 317–329 (2009).

  107. 107.

    Kusafuka, T., Miao, J., Kuroda, S., Udatsu, Y. & Yoneda, A. Codon 45 of the β-catenin gene, a specific mutational target site of Wilms’ tumor. Int. J. Mol. Med. 10, 395–399 (2002).

  108. 108.

    Amit, S. et al. Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 16, 1066–1076 (2002).

  109. 109.

    Perlman, E. J. et al. MLLT1 YEATS domain mutations in clinically distinctive favourable histology Wilms tumours. Nat. Commun. 6, 10013 (2015).

  110. 110.

    Ui, A. & Yasui, A. Collaboration of MLLT1/ENL, polycomb and ATM for transcription and genome integrity. Nucleus 7, 138–145 (2016).

  111. 111.

    Hodges, C., Kirkland, J. G. & Crabtree, G. R. The many roles of BAF (mSWI/SNF) and PBAF complexes in cancer. Cold Spring Harb. Perspect. Med. 6, a026930 (2016).

  112. 112.

    Parsons, D. W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011).

  113. 113.

    Hasselblatt, M. et al. Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am. J. Surg. Pathol. 35, 933–935 (2011).

  114. 114.

    Network, T. C. G. A. R. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013).

  115. 115.

    Abell, A. N. et al. MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells. Cell Stem Cell 8, 525–537 (2011).

  116. 116.

    Huynh, K. D., Fischle, W., Verdin, E. & Bardwell, V. J. BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev. 14, 1810–1823 (2000).

  117. 117.

    Pagan, J. K. et al. A novel corepressor, BCoR-L1, represses transcription through an interaction with CtBP. J. Biol. Chem. 282, 15248–15257 (2007).

  118. 118.

    Yamamoto, Y., Abe, A. & Emi, N. Clarifying the impact of polycomb complex component disruption in human cancers. Mol. Cancer Res. 12, 479–484 (2014).

  119. 119.

    Shiba, N. et al. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. Br. J. Haematol. 175, 476–489 (2016).

  120. 120.

    Roy, A. et al. Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat. Commun. 6, 8891 (2015).

  121. 121.

    Liu, P. Y. et al. Effects of a novel long noncoding RNA, lncUSMycN, on N-Myc expression and neuroblastoma progression. 106, dju113 (2014).

  122. 122.

    Cascon, A. & Robledo, M. MAX and MYC: a heritable breakup. Cancer Res. 72, 3119–3124 (2012).

  123. 123.

    Ferrucci, F. et al. MAX to MYCN intracellular ratio drives the aggressive phenotype and clinical outcome of high risk neuroblastoma. Biochim. Biophys. Acta Gene Regul. Mech. 1861, 235–245 (2018).

  124. 124.

    Xu, B. et al. Tumor suppressor menin represses paired box gene 2 expression via Wilms tumor suppressor protein-polycomb group complex. J. Biol. Chem. 286, 13937–13944 (2011).

  125. 125.

    Russell, B. et al. Clinical management of patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing the need for Wilms tumor surveillance. Am. J. Med. Genet. Part A 167, 2122–2131 (2015).

  126. 126.

    Mengelbier, L. H. et al. Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer. Nat. Commun. 6, 6125 (2015).

  127. 127.

    Williams, R. D. et al. Molecular profiling reveals frequent gain of MYCN and anaplasia-specific loss of 4q and 14q in wilms tumor. Genes Chromosomes Cancer 50, 982–995 (2011).

  128. 128.

    Williams, R. D. et al. Multiple mechanisms of MYCN dysregulation in Wilms tumour. Oncotarget 6, 7232–7243 (2015).

  129. 129.

    Urbach, A. et al. Lin28 sustains early renal progenitors and induces Wilms tumor. Genes Dev. 28, 971–982 (2014).

  130. 130.

    Nagalakshmi, V. K. et al. Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney. Kidney Int. 79, 317–330 (2011).

  131. 131.

    Ruf, R. G. et al. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc. Natl Acad. Sci. USA 101, 8090–8095 (2004).

  132. 132.

    Xu, P.-X. et al. Six1 is required for the early organogenesis of mammalian kidney. Development 130, 3085–3094 (2003).

  133. 133.

    Self, M. et al. Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney. EMBO J. 25, 5214–5228 (2006).

  134. 134.

    Rivera, M. N. et al. An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 315, 642–645 (2007).

  135. 135.

    Beltran, H. The N-myc oncogene: maximizing its targets, regulation, and therapeutic potential. Mol. Cancer Res. 12, 815–822 (2014).

  136. 136.

    Gustafson, W. C. et al. Drugging MYCN through an allosteric transition in aurora kinase A. Cancer Cell 26, 414–427 (2014).

  137. 137.

    Brok, J., Pritchard-Jones, K., Geller, J. I. & Spreafico, F. Review of phase I and II trials for Wilms’ tumour – can we optimise the search for novel agents? Eur. J. Cancer 79, 205–213 (2017).

  138. 138.

    Wetmore, C. et al. Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children. Neuro. Oncol. 17, 882–888 (2015).

  139. 139.

    DuBois, S. G. et al. Phase I study of the aurora A kinase inhibitor alisertib in combination with irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma: a NANT (new approaches to neuroblastoma therapy) trial. J. Clin. Oncol. 34, 1368–1375 (2016).

  140. 140.

    Yaari, S. et al. Disruption of cooperation between Ras and MycN in human neuroblastoma cells promotes growth arrest. Clin. Cancer Res. 11, 4321–4330 (2005).

  141. 141.

    Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).

  142. 142.

    O’Bryan, J. P. Pharmacological targeting of RAS: recent success with direct inhibitors. Pharmacol. Res. (2018).

  143. 143.

    Dalpa, E., Gourvas, V., Soulitzis, N. & Spandidos, D. A. K-Ras, H-Ras, N-Ras and B-Raf mutation and expression analysis in Wilms tumors: association with tumor growth. Med. Oncol. 34, 6 (2017).

  144. 144.

    Clark, P. E. et al. β-Catenin and K-RAS synergize to form primitive renal epithelial tumors with features of epithelial Wilms’ tumors. Am. J. Pathol. 179, 3045–3055 (2011).

  145. 145.

    Cramer, S. L. et al. Pediatric anaplastic embryonal rhabdomyosarcoma: targeted therapy guided by genetic analysis and a patient-derived xenograft study. Front. Oncol. 7, 327 (2018).

  146. 146.

    Liu, H. et al. Histone deacetylases 1 and 2 regulate the transcriptional programs of nephron progenitors and renal vesicles. Development 145, dev153619 (2018).

  147. 147.

    Burgess, A. et al. Clinical overview of MDM2/X-targeted therapies. Front. Oncol. 6, 7 (2016).

  148. 148.

    Wood, A. C. et al. Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program. Pediatr. Blood Cancer 60, 1860–1867 (2013).

  149. 149.

    US National Library of Medicine. (2018).

  150. 150.

    Markovsky, E. et al. Wilms tumor NCAM-expressing cancer stem cells as potential therapeutic target for polymeric nanomedicine. Mol. Cancer Ther. 16, 2462–2472 (2017).

  151. 151.

    US National Library of Medicine. (2018).

  152. 152.

    Essafi, A. et al. A Wt1-controlled chromatin switching mechanism underpins tissue-specific Wnt4 activation and repression. Dev. Cell 21, 559–574 (2011).

  153. 153.

    Park, J.-S. et al. Six2 and Wnt regulate self-renewal and commitment of nephron progenitors through shared gene regulatory networks. Dev. Cell 23, 637–651 (2012).

  154. 154.

    Dong, L., Pietsch, S. & Englert, C. Towards an understanding of kidney diseases associated with WT1 mutations. Kidney Int. 88, 684–690 (2015).

  155. 155.

    Walker, K. A., Sims-Lucas, S. & Bates, C. M. Fibroblast growth factor receptor signaling in kidney and lower urinary tract development. Pediatr. Nephrol. 31, 885–895 (2016).

  156. 156.

    Denner, D. R. & Rauchman, M. Mi-2/NuRD is required in renal progenitor cells during embryonic kidney development. Dev. Biol. 375, 105–116 (2013).

  157. 157.

    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).

  158. 158.

    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).

  159. 159.

    Yost, S. et al. Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation. Nat. Genet. 49, 1148–1151 (2017).

  160. 160.

    Soejima, H. & Higashimoto, K. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. J. Hum. Genet. 58, 402–409 (2013).

  161. 161.

    Sanz, M. M., German, J. & Cunniff, C. in GeneReviews® (Univ. of Washington, Seattle, 1993).

  162. 162.

    Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

  163. 163.

    Shuman, C. et al. Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies. Am. J. Med. Genet. A 140A, 1497–1503 (2006).

  164. 164.

    Karlberg, N. et al. High frequency of tumours in Mulibrey nanism. J. Pathol. 218, 163–171 (2009).

  165. 165.

    Gripp, K. W. et al. Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. Am. J. Med. Genet. Part A 170, 2559–2569 (2016).

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The authors thank G. M. Vujanic (Sidra Medicine) for kindly providing the Wilms tumour histology images used in Figure 1. T.T. is funded by a Cambridge Academic Clinical Fellowship. S.B. is funded through personal awards from the Wellcome Trust and the St. Baldrick’s Foundation. K.P.J. is funded in part by the National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital, the Great Ormond Street Hospital Children’s Charity and Cancer Research UK (grant no. C1188/A4614).

Reviewer information

Nature Reviews Nephrology thanks A. Reeve and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Wellcome Sanger Institute, Cambridge, UK

    • Taryn Dora Treger
    •  & Sam Behjati
  2. Department of Paediatrics, University of Cambridge, Cambridge, UK

    • Taryn Dora Treger
    •  & Sam Behjati
  3. UCL Great Ormond Street Institute of Child Health, London, UK

    • Taryn Dora Treger
    •  & Kathy Pritchard-Jones
  4. Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

    • Tanzina Chowdhury
    • , Kathy Pritchard-Jones
    •  & Sam Behjati


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All authors researched the data for the article, contributed to discussions of the content, wrote the text and reviewed or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Kathy Pritchard-Jones.



A rudimentary organ in the earliest stage of development during embryogenesis.

Mesenchymal-to-epithelial transition

(MET). The alteration of a cell phenotype from a mesenchymal state to epithelia.


The partial or complete absence of the iris.


A rare gonadal tumour with a mixture of germ and sex cord stromal cells.

Uniparental disomy

A chromosomal disorder whereby the chromosome pair is inherited from one parent.

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