Predisposition footprints in the somatic genome of Wilms tumours

Menée sur une cohorte de 137 enfants atteints d'une tumeur de Wilms (dont 71 enfants avec mutation mosaïque ou variant constitutionnel pathogènes) et à partir de l'analyse de 237 néoplasies (dont 2 leucémies secondaires), cette étude démontre que l'évolution somatique de la tumeur dépend du variant génétique

Résumé en anglais

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), utilising WGS, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed in children harbouring 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. Our findings indicate that predisposition may preordain Wilms tumourigenesis, suggesting a variant specific approach to managing children merits consideration.