Genome-wide sequencing, mRNA and miRNA expression, DNA copy number and methylation analyses were performed on 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, FAM123B, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), mutations were identified in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and let-7a loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

Paediatric renal tumours account for ~6% of all paediatric malignant tumours, of which ~90% are Wilms tumours (nephroblastoma) 1. Other renal non-Wilms tumours are rare entities and include mesoblastic nephroma, clear cell sarcoma of the kidney, rhabdoid tumour of the kidney, renal cell carcinoma and few other, even rarer tumour types 1. The Renal Tumour Study Group of the International Society of Paediatric Oncology (SIOP-RTSG) has developed a new study for all renal tumours of childhood, the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol) 2,3 , on the basis of the experiences from SIOP-2001 and the UK Improving Population Outcomes for Renal Tumours of Childhood (IMPORT) 2013 studies 2-4. The aim of the UMBRELLA protocol is to collect all clinical, biological and outcomes data from children with primary renal tumours in a comprehensive data registry, with central review of diagnostics (radiology, patho logy and surgery), standardized biobanking and precise treatment recommendations for the most common paediatric renal tumours. Molecular biology research within the protocol is primarily focused on the validation of the prognostic value of 1q gain, which might lead to a more personalized treatment approach (Box 1). Consequently, short-term and long-term outcomes might be improved for all children with renal tumours by increasing survival, but also by reducing treatment in specific subgroups, resulting in diminished direct and late adverse effects. Timely genetic analysis and step-wise extension to additional targets such as TP53 (refs 5-7) or several of the newly identified driver candidates for stratification and inclusion of liquid biopsies might help to reach this goal 8-10. The UMBRELLA protocol includes updated guidelines for pathologists for the handling and processing of tissue as well as criteria that are important for postoperative histological classification, staging and treatment stratification. These recommendations were established by a consensus of pathology experts within the SIOP-RTSG (chaired by G. M. Vujanić and I. Leuschner).

SUMMARY We report the most common single nucleotide substitution/deletion mutations in Favorable Histology Wilms Tumors (FHWT) to occur within SIX1/2 (7% of 534 tumors) and microRNA processing genes (miRNAPG) DGCR8 and DROSHA (15% of 534 tumors). Comprehensive analysis of 77 FHWTs indicates that tumors with SIX1/2 and/or miRNAPG mutations show a pre-induction metanephric mesenchyme gene expression pattern and are significantly associated with both perilobar nephrogenic rests and 11p15 imprinting aberrations. Significantly decreased expression of mature Let-7a and the miR-200 family (responsible for mesenchymal-to-epithelial transition) in miRNAPG-mutant tumors is associated with an undifferentiated blastemal histology. The combination of SIX and miRNAPG mutations in the same tumor is associated with evidence of RAS activation and a higher rate of relapse and death.