Wilms tumour (WT) is the most common renal tumour of infants and young children 1,2 . WT is inti- mately linked to early nephrogenesis, which it resem- bles morphologically 3 and transcriptionally 4,5 . WT may occur sporadically or in the context of bilateral tumours, multifocal disease and specified genetic predisposition syndromes that frequently include either genitourinary malformation or overgrowth 3 . Beyond genetic pre- disposition, external causative factors for WT are not yet defined. The molecular drivers frequently involve blockade of genetic pathways that guide normal embryo- genesis of the genitourinary tract but are not restricted to these. Indeed, the cancer genes that underpin WT are diverse and surprisingly involve ~40 genes. The implementation of international co-operative group trials and studies across North America, Australia, New Zealand, Europe and Brazil has contributed sig- nificantly to improving outcomes 6–8 . Two interna- tional multidisciplinary cooperative consortia — the Children’s Oncology Group (COG) Renal Tumour Committee, previously known as the National Wilms Tumour Study Group (NWTSG), and the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group (RTSG) — have conducted large multi- centre studies since 1969 and 1971, respectively, which have defined the current diagnostic and therapeutic approach to patients with WT (FIG. 1). These groups continue research to optimize disease and patient risk classification and treatment strategies 9–11 . In the COG, WTs are treated with primary resection (if possible), followed by risk-adapted adjuvant therapy, whereas in the context of SIOP cooperation, neoadju- vant chemotherapy followed by resection and adjuvant therapy is the preferred treatment approach. Regardless of the initial approach, the overall survival of children with WT is remarkable with rates of >90%. Such satisfy- ing survival rates have been achieved at the same time as fine-tuning treatment by adopting well-studied prognos- tic factors, leading to a two-drug regimen (vincristine and actinomycin D) prescribed in nearly two-thirds of affected children 7,10 . Notably, striking survival disparities still exist within countries 12 and between different parts of the world, which remain to be addressed 13,14 . However, 20% of patients relapse after first-line therapy and up to 25% of survivors report severe late morbidity of treatment 15,16 . Addressing the long-term effect of radical nephrectomy on renal function and cardiovascular func- tion will probably drive more attention on expanding the role of nephron-sparing surgery (NSS) 17 . Molecular studies are expanding the landscape of cancer genes implicated in WT beyond exclusive roles in nephrogenesis 3 . The use of next- generation Nephron-sparing surgery An operation to remove a kidney tumour by removing only part of the surrounding normal renal parenchyma. Wilms tumour Filippo Spreafico 1 ✉ , Conrad V. Fernandez 2 , Jesper Brok 3 , Kayo Nakata 4 , Gordan Vujanic 5 , James I. Geller 6 , Manfred Gessler 7 , Mariana Maschietto 8 , Sam Behjati 9,10,11 , Angela Polanco 12 , Vivian Paintsil 13 , Sandra Luna-Fineman 14 and Kathy Pritchard-Jones 15 Abstract | Wilms tumour (WT) is a childhood embryonal tumour that is paradigmatic of the intersection between disrupted organogenesis and tumorigenesis. Many WT genes play a critical (non-redundant) role in early nephrogenesis. Improving patient outcomes requires advances in understanding and targeting of the multiple genes and cellular control pathways now identified as active in WT development. Decades of clinical and basic research have helped to gradually optimize clinical care. Curative therapy is achievable in 90% of affected children, even those with disseminated disease, yet survival disparities within and between countries exist and deserve commitment to change. Updated epidemiological studies have also provided novel insights into global incidence variations. Introduction of biology-driven approaches to risk stratification and new drug development has been slower in WT than in other childhood tumours. Current prognostic classification for children with WT is grounded in clinical and pathological findings and in dedicated protocols on molecular alterations. Treatment includes conventional cytotoxic chemotherapy and surgery, and radiation therapy in some cases. Advanced imaging to capture tumour composition, optimizing irradiation techniques to reduce target volumes, and evaluation of newer surgical procedures are key areas for future research. ✉ e-mail: filippo.spreafico@ istitutotumori.mi.it https://doi.org/10.1038/ s41572-021-00308-8 1 PRIMER NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:75 0123456789();: