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Hallmark discoveries in the biology of Wilms tumour

Nature Reviews Urology volume 21, pages 158–180 (2024)Cite this article

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Abstract

The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the ‘two-hit’ model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics — from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions.

Key points

  • The genetic landscape of Wilms tumours has been deeply investigated, but the relationship to intratumoural heterogeneity and how abnormal nephrogenesis relates to malignant transformation to Wilms tumour are still being explored.

  • Genetics of the classical syndromic conditions associated with Wilms tumour development have been described in detail, but whole-exome sequencing is revealing a wide range of constitutional mutations in children that lack any clear phenotype.

  • Prognostic biomarkers are starting to be used in clinical practice and for risk stratification in trials, but more need to be identified and validated.

  • Many complementary preclinical Wilms tumour models are now available.

  • Efforts to explore the events that lead to aggressive and/or recurrent disease are needed.

  • Worldwide international collaborations between experts in the field have been established.

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Fig. 1: Key discoveries in Wilms tumour biology.
Fig. 2: Nephrogenic rest.
Fig. 3: Diffuse anaplasia in Wilms tumour.
Fig. 4: Blastemal Wilms tumour.
Fig. 5: Evolutionary trajectories in Wilms tumour.

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Author notes

  1. These authors contributed equally: Daniela Perotti, Richard D. Williams, Jenny Wegert, Jack Brzezinski, Mariana Maschietto, Sara Ciceri, David Gisselsson, Samantha Gadd, Amy L. Walz, Rhoikos Furtwaengler, Jarno Drost, Reem Al-Saadi, Nicholas Evageliou, Saskia L. Gooskens, Andrew L. Hong, Andrew J. Murphy, Michael V. Ortiz, Maureen J. O’Sullivan, Elizabeth A. Mullen, Marry M. van den Heuvel-Eibrink, Conrad V. Fernandez, Norbert Graf, Paul E. Grundy, James I. Geller, Jeffrey S. Dome, Elizabeth J. Perlman, Manfred Gessler, Vicki Huff, Kathy Pritchard-Jones.

Authors and Affiliations

  1. Predictive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Daniela Perotti & Sara Ciceri

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

    Richard D. Williams, Reem Al-Saadi & Kathy Pritchard-Jones

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

    Richard D. Williams

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

    Jenny Wegert & Manfred Gessler

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

    Jack Brzezinski

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

    Jack Brzezinski

  7. Research Center, Boldrini Children’s Hospital, Campinas, São Paulo, Brazil

    Mariana Maschietto

  8. Cancer Cell Evolution Unit, Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden

    David Gisselsson

  9. Clinical Genetics, Pathology and Molecular Diagnostics, Office of Medical Services, Skåne, Sweden

    David Gisselsson

  10. Department of Pathology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Samantha Gadd & Elizabeth J. Perlman

  11. Division of Hematology,Oncology, Neuro-Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA

    Amy L. Walz

  12. Division of Pediatric Oncology and Hematology, Department of Pediatrics, Inselspital Bern University, Bern, Switzerland

    Rhoikos Furtwaengler

  13. Princess Máxima Center for Paediatric Oncology, Utrecht, Netherlands

    Jarno Drost, Saskia L. Gooskens & Marry M. van den Heuvel-Eibrink

  14. Oncode Institute, Utrecht, Netherlands

    Jarno Drost

  15. Department of Histopathology, Great Ormond Street Hospital for Children, London, UK

    Reem Al-Saadi

  16. Divisions of Hematology and Oncology, Children’s Hospital of Philadelphia, CHOP Specialty Care Center, Vorhees, NJ, USA

    Nicholas Evageliou

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

    Andrew L. Hong

  18. Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Andrew J. Murphy

  19. Department of Paediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Michael V. Ortiz

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

    Maureen J. O’Sullivan

  21. Trinity Translational Medicine Institute, Trinity College, Dublin, Ireland

    Maureen J. O’Sullivan

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

    Elizabeth A. Mullen

  23. Division of Paediatric Hematology Oncology, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada

    Conrad V. Fernandez

  24. Department of Paediatric Oncology and Hematology, Saarland University Hospital, Homburg, Germany

    Norbert Graf

  25. Department of Paediatrics Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada

    Paul E. Grundy

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

    James I. Geller

  27. Division of Oncology, Center for Cancer and Blood Disorders, Children’s National Hospital and the Department of Paediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    Jeffrey S. Dome

  28. Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany

    Manfred Gessler

  29. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Vicki Huff

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The authors contributed equally to all aspects of the article.

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Correspondence to Daniela Perotti.

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Nature Reviews Urology thanks Arnauld Verschuur, Jonathan Routh and Rafael Tua-Caraccia for their contribution to the peer review of this work.

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Perotti, D., Williams, R.D., Wegert, J. et al. Hallmark discoveries in the biology of Wilms tumour. Nat Rev Urol 21, 158–180 (2024). https://doi.org/10.1038/s41585-023-00824-0

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