The genetic changes of Wilms tumour

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Abstract

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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Fig. 1: Features of Wilms tumour histology.
Fig. 2: The role of Wilms tumour genes in nephrogenesis.

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Acknowledgements

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.

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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.

Correspondence to Kathy Pritchard-Jones.

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Glossary

Anlage

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.

Aniridia

The partial or complete absence of the iris.

Gonadoblastoma

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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Treger, T.D., Chowdhury, T., Pritchard-Jones, K. et al. The genetic changes of Wilms tumour. Nat Rev Nephrol 15, 240–251 (2019) doi:10.1038/s41581-019-0112-0

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