Somatic development of Wilms tumour via normal kidneys in predisposed children

Ten percent of children with cancer harbour a predisposition mutation. 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 tumour genetic development. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic predisposition. We examined 237 neoplasms (including two secondary leukaemias), utilising whole genome sequencing, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed between predisposed and sporadic cases, and amongst predisposed children according to specific mutations and their 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 the development of Wilms tumour, suggesting that a variant specific approach to the management of these children merits consideration. STATEMENT OF SIGNIFICANCETumours that arise in children with a cancer predisposition may, or may not, develop through the same mutational pathways as sporadic tumours. We examined this question in the childhood kidney cancer, Wilms tumour. We found that some predispositions strongly constrain the genetic development of tumours, which may have clinical implications.