Somatic development of Wilms tumour via normal kidneys in predisposed children

Ten percent of children with cancer harbour a mutation in a predisposition gene. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumourigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukaemias) from the cohort, utilising whole genome sequencing, RNA sequencing and genome wide methylation, validating our findings in an independent cohort of 21 children. The development of tumours differed between children with sporadic disease and amongst those with a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Predisposition constrains Wilms tumourigenesis, suggesting a variant specific approach to managing these children merits consideration. We analysed methylation data from 455 samples (normal kidney tissue, blood and tumour) from 137 children with Wilms tumour as part of a study to investigate how tumour development differs between chldren predisposed to Wilms tumour and chidlren with sporadic disease.