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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is part of The Little Princess Trust Knowledge Bank of Wilms Tumour funded by The Little Princess Trust. Additional funding was provided by the Wellcome Trust (personal fellowship to S.B., institutional grant to the Wellcome Sanger Institute; references 220540/Z/20/A and 223135/Z/21/Z), the Wenner-Gren Foundations (personal fellowship to A.W.) and the Pessoa de Araujo family (personal fellowship to A.H.). This research was supported by the NIHR GOSH Biomedical Research Centre and NIHR Cambridge Biomedical Research Centre (NIHR203312). Within Germany the SIOP 2001 study and trial was supported by Deutsche Krebshilfe (grant 50-2709-Gr2). Work in the lab of M.G. was supported by the DFG (Ge539) and the Wilhelm-Sander-Stiftung. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We obtained samples from these sources: the UK Improving Population Outcomes for Renal Tumours of Childhood (IMPORT) study, now known as UMBRELLA (approved by an NHS research ethics committee, references London Bridge REC 12/LO/0101); the German arm of the SIOP 2001 study (EudraCT number SIOP 2001: 2007-004591-39, approved by Ethik-Kommission der Arztekammer des Saarlandes, approval numbers 136/01 and 248/13); and the Netherlands (approved by Medisch Ethische Toestings Commissie ErasmucMC, approval numbers MEC 202.134/2001/122, MEC-2018-026, MEC-2006-348 and Netherlands Trial Register NL7744 MEC-2016-739). Institutional archive and biobank consent was provided by the institutional biobank committee of the Princes Maxima Centre, Utrecht. PD IDs are de-identified and unknown to anyone. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Raw DNA data generated in this study have been deposited in the European Genome-Phenome Archive (EGA) under accession code EGAS00001004237. Raw RNA data generated in this study have been deposited in the European Genome-Phenome Archive (EGA) under accession code EGAS00001005244.