High resolution clonal architecture of hypomutated Wilms tumours

Henry Lee-Six, Taryn D. Treger, Manas Dave, Tim HH Coorens, Nathaniel D. Anderson, Yvonne Tiersma, Sepide Derakhshan, Sanne Haan, Marry M. Heuvel-Eibrink, Yichen Wang, Anna Wenger, Reem Al-Saadi, Alice Lawford, Aleksandra Letunovska, Jenny Wegert, Conor Parks, Guillaume Morcrette, Manfred Gessler, Gordan Vujanic, Tanzina Chowdhury, Maureen J O’Sullivan, Ronald R. Krijger, Michael R. Stratton, Kathy Pritchard-Jones, J. Ciaran Hutchinson (), Jarno Drost () and Sam Behjati ()
Additional contact information
Henry Lee-Six: Wellcome Sanger Institute
Taryn D. Treger: Wellcome Sanger Institute
Manas Dave: Wellcome Sanger Institute
Tim HH Coorens: Broad Institute of MIT and Harvard
Nathaniel D. Anderson: Wellcome Sanger Institute
Yvonne Tiersma: Princess Máxima Center for Pediatric Oncology
Sepide Derakhshan: Princess Máxima Center for Pediatric Oncology
Sanne Haan: Princess Máxima Center for Pediatric Oncology
Marry M. Heuvel-Eibrink: Princess Máxima Center for Pediatric Oncology
Yichen Wang: Wellcome Sanger Institute
Anna Wenger: Wellcome Sanger Institute
Reem Al-Saadi: UCL Great Ormond Street Institute of Child Health
Alice Lawford: Great Ormond Street Hospital for Children
Aleksandra Letunovska: UCL Great Ormond Street Institute of Child Health
Jenny Wegert: Würzburg University & Comprehensive Cancer Center Mainfranken
Conor Parks: Wellcome Sanger Institute
Guillaume Morcrette: UCL Great Ormond Street Institute of Child Health
Manfred Gessler: Würzburg University & Comprehensive Cancer Center Mainfranken
Gordan Vujanic: Sidra Medicine
Tanzina Chowdhury: UCL Great Ormond Street Institute of Child Health
Maureen J O’Sullivan: Children’s Health Ireland at Crumlin
Ronald R. Krijger: Princess Máxima Center for Pediatric Oncology
Michael R. Stratton: Wellcome Sanger Institute
Kathy Pritchard-Jones: UCL Great Ormond Street Institute of Child Health
J. Ciaran Hutchinson: Great Ormond Street Hospital for Children
Jarno Drost: Princess Máxima Center for Pediatric Oncology
Sam Behjati: Wellcome Sanger Institute

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: Abstract A paradigm of childhood cancers is that they have a low mutation burden, with some ostensibly bearing fewer mutations than the normal tissues from which they derive. We set out to resolve this paradox by examining paediatric renal cancers with exceptionally few mutations using high resolution, high depth sequencing approaches. We find that apparent hypomutation is the result of unusual clonal architecture due to a normal tissue-like mode of tumour evolution, raising the possibility that the mutation burden of some cancers has been systematically misjudged.

Date: 2025
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DOI: 10.1038/s41467-025-59854-4

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