The genetic changes of Wilms tumour

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.Wilms tumour is the most common renal malignancy of childhood. Here, the authors review the genetic landscape of Wilms tumour and discuss how precision medicine guided by genomic information might lead to new therapeutic approaches and improve patient survival.Key pointsWilms 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.