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Hallmark discoveries in the biology of non-Wilms tumour childhood kidney cancers

Nature Reviews Urology (2025)Cite this article

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Abstract

Approximately 20% of paediatric and adolescent/young adult patients with renal tumours are diagnosed with non-Wilms tumour, a broad heterogeneous group of tumours that includes clear-cell sarcoma of the kidney, congenital mesoblastic nephroma, malignant rhabdoid tumour of the kidney, renal-cell carcinoma, renal medullary carcinoma and other rare histologies. The differential diagnosis of these tumours dates back many decades, when these pathologies were identified initially through clinicopathological observation of entities with outcomes that diverged from Wilms tumour, corroborated with immunohistochemistry and molecular cytogenetics and, subsequently, through next-generation sequencing. These advances enabled near-definitive recognition of different tumours and risk stratification of patients. In parallel, the generation of new renal-tumour models of some of these pathologies including cell lines, organoids, xenografts and genetically engineered mouse models improved our understanding of the development of these tumours and have facilitated the identification of new therapeutic targets. Despite these many achievements, paediatric and adolescent/young adult patients continue to die from such rare cancers at higher rates than patients with Wilms tumour. Thus, international coordinated efforts are needed to answer unresolved questions and improve outcomes.

Key points

  • Non-Wilms tumours occur in ~20% of paediatric and adolescent/young adult patients with kidney cancers, and advances in next-generation sequencing have brought clarity to this group of rare and hard-to-treat cancers.

  • Translocation renal-cell carcinomas are primarily driven by translocations involving the MiT family members TFE3, TFEB and ELOC. A growing number of cell lines and patient-derived xenograft (PDX) models are available for these tumours, but genetically modified mouse models remain a gap in the field.

  • Renal medullary carcinomas are characterized by a biallelic loss of SMARCB1 and generally include a disruptive balanced translocation of one SMARCB1 allele. Robust models of renal medullary carcinomas (such as cell lines, organoids and PDXs) are now available or actively being developed.

  • Malignant rhabdoid tumours of the kidney are driven by biallelic loss of SMARCB1 and, to a lesser extent, SMARCA4. Here, there are a relatively large number of cell lines, organoids, PDX and genetically modified mouse models that are available for these tumours, which led to identification of several potential therapeutic targets.

  • Clear-cell sarcoma of the kidney, congenital mesoblastic nephromas and most of the other paediatric and adolescent and young adult non-Wilms renal tumours are driven by alterations in BCOR, EGFR, DICER1, BRAF and TSC1 or TSC2, along with gene fusions involving EWSR and NTRK. This group of tumours is in need of preclinical models. International collaborations will lead to the establishment of these models and the development of functional studies to facilitate the identification of therapeutic targets, ultimately resulting in informed clinical trials and improved outcomes.

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Fig. 1: Molecular and histological advances in the study of translocation renal-cell carcinomas.
Fig. 2: Molecular and histological advances in the study of renal medullary carcinoma.
Fig. 3: Molecular and histological advances in the study of malignant rhabdoid tumour of the kidney.
Fig. 4: Molecular and histological advances in the study of clear-cell sarcoma of the kidney.
Fig. 5: Molecular and histological advances in the study of congenital mesoblastic nephroma.
Fig. 6: Histology of other non-Wilms renal tumours.

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Author notes

  1. These authors contributed equally: Daniela Perotti, Maureen J. O’Sullivan.

Authors and Affiliations

  1. Predictive Medicine: Molecular Bases of Genetic Risk, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

    Daniela Perotti & Sara Ciceri

  2. Histology Laboratory, Children’s Health Ireland at Crumlin, Dublin, Ireland

    Maureen J. O’Sullivan

  3. Histopathology, School of Medicine, Trinity College, Dublin, Ireland

    Maureen J. O’Sullivan

  4. Departments of Histopathology and Paediatrics, School of Medicine, Trinity College Dublin, Dublin, Ireland

    Maureen J. O’Sullivan

  5. Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Amy L. Walz

  6. University of Iowa Hospitals and Clinics Stead Family Children’s Hospital, Carver College of Medicine, Iowa City, IA, USA

    Jonathan Davick

  7. UCL Great Ormond Street Institute of Child Health, University College London, London, UK

    Reem Al-Saadi

  8. Division of Pediatric Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA

    Daniel J. Benedetti

  9. Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada

    Jack Brzezinski

  10. Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada

    Jack Brzezinski

  11. Department of Surgery, Division of Urology, University of Colorado School of Medicine and the Surgical Oncology Program at Children’s Hospital Colorado, Denver, CO, USA

    Nicholas G. Cost

  12. Division of Oncology, Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DC, USA

    Jeffrey S. Dome

  13. Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Jeffrey S. Dome

  14. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands

    Jarno Drost & Justine N. van der Beek

  15. Oncode Institute, Utrecht, the Netherlands

    Jarno Drost

  16. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Nicholas Evageliou

  17. Pediatric Hematology and Oncology, Children’s Hospital, Inselspital Bern University, Bern, Switzerland

    Rhoikos Furtwängler

  18. Childhood Renal Tumour Center Saarland University, Homburg, Germany

    Rhoikos Furtwängler

  19. Department Paediatric Oncology & Hematology, Saarland University, Homburg, Germany

    Norbert Graf

  20. Research Center, Boldrini Children’s Hospital, Campinas, SP, Brazil

    Mariana Maschietto

  21. Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA

    Elizabeth A. Mullen

  22. St. Jude Children’s Research Hospital Memphis, Memphis, TN, USA

    Andrew J. Murphy

  23. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Michael V. Ortiz

  24. University Medical Center Utrecht, Utrecht, the Netherlands

    Justine N. van der Beek & Marry M. van den Heuvel-Eibrink

  25. Department of Pediatric Hematology and Oncology, Hôpital d’Enfants de la Timone, APHM, Marseille, France

    Arnauld Verschuur

  26. Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, Wuerzburg University, Wuerzburg, Germany

    Jenny Wegert

  27. Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, UK

    Richard Williams

  28. Section of Genetics and Genomics, Faculty of Medicine, Imperial College London, London, UK

    Richard Williams

  29. Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

    Filippo Spreafico

  30. Division of Oncology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA

    James I. Geller

  31. Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA

    Andrew L. Hong

  32. Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Andrew L. Hong

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  1. Daniela Perotti
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Contributions

All authors researched data for the article. A.L.H., D.P., M.J.O.S., A.L.W., J.D., J.I.G. and M.M.V.D.H.E. contributed substantially to discussion of the content. All authors wrote the article. A.L.H., D.P., M.J.O.S., A.L.W., J.D., D.J.B., N.G.C., J.S.D., E.A.M., A.J.M., M.V.O., J.N.V.D.B., J.W., F.S., J.I.G. and M.M.V.D.H.E. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Andrew L. Hong.

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N.G.C.’s spouse is a Senior Medical Officer for Jannsen. The other authors declare no competing interests.

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Nature Reviews Urology thanks Harold Lovvorn and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Perotti, D., O’Sullivan, M.J., Walz, A.L. et al. Hallmark discoveries in the biology of non-Wilms tumour childhood kidney cancers. Nat Rev Urol (2025). https://doi.org/10.1038/s41585-024-00993-6

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