High resolution clonal architecture of hypomutated Wilms tumours

Henry Lee-Six; Taryn D. Treger; Manas Dave; Tim H.H. Coorens; Nathaniel D. Anderson; Yvonne Tiersma; Sepide Derakhshan; Sanne de Haan; Marry M. van den 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. de Krijger; Michael R. Stratton; Kathy Pritchard-Jones; J. Ciaran Hutchinson; Jarno Drost; Sam Behjati

doi:10.1038/s41467-025-59854-4

High resolution clonal architecture of hypomutated Wilms tumours

Henry Lee-Six, Taryn D. Treger, Manas Dave, Tim H.H. Coorens, Nathaniel D. Anderson, Yvonne Tiersma, Sepide Derakhshan, Sanne de Haan, Marry M. van den Heuvel-Eibrink, Yichen Wang, Anna Wenger, Reem Al-Saadi, Alice Lawford, Aleksandra Letunovska, Jenny Wegert, Conor Parks, Guillaume Morcrette, Manfred Gessler, Gordan Vujanic, Tanzina ChowdhuryMaureen J O’Sullivan, Ronald R. de Krijger, Michael R. Stratton, Kathy Pritchard-Jones, J. Ciaran Hutchinson^*, Jarno Drost^*, Sam Behjati^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	4647
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-59854-4
Publication status	Published - Dec 2025

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Lee-Six, H., Treger, T. D., Dave, M., Coorens, T. H. H., Anderson, N. D., Tiersma, Y., Derakhshan, S., de Haan, S., van den Heuvel-Eibrink, M. M., Wang, Y., Wenger, A., Al-Saadi, R., Lawford, A., Letunovska, A., Wegert, J., Parks, C., Morcrette, G., Gessler, M., Vujanic, G., ... Behjati, S. (2025). High resolution clonal architecture of hypomutated Wilms tumours. Nature Communications, 16(1), Article 4647. https://doi.org/10.1038/s41467-025-59854-4

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title = "High resolution clonal architecture of hypomutated Wilms tumours",

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.",

author = "Henry Lee-Six and Treger, \{Taryn D.\} and Manas Dave and Coorens, \{Tim H.H.\} and Anderson, \{Nathaniel D.\} and Yvonne Tiersma and Sepide Derakhshan and \{de Haan\}, Sanne and \{van den Heuvel-Eibrink\}, \{Marry M.\} and Yichen Wang and Anna Wenger and Reem Al-Saadi and Alice Lawford and Aleksandra Letunovska and Jenny Wegert and Conor Parks and Guillaume Morcrette and Manfred Gessler and Gordan Vujanic and Tanzina Chowdhury and \{J O{\textquoteright}Sullivan\}, Maureen and \{de Krijger\}, \{Ronald R.\} and Stratton, \{Michael R.\} and Kathy Pritchard-Jones and Hutchinson, \{J. Ciaran\} and Jarno Drost and Sam Behjati",

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year = "2025",

month = dec,

doi = "10.1038/s41467-025-59854-4",

language = "English",

volume = "16",

journal = "Nature Communications",

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Lee-Six, H, Treger, TD, Dave, M, Coorens, THH, Anderson, ND, Tiersma, Y, Derakhshan, S, de Haan, S, van den Heuvel-Eibrink, MM, Wang, Y, Wenger, A, Al-Saadi, R, Lawford, A, Letunovska, A, Wegert, J, Parks, C, Morcrette, G, Gessler, M, Vujanic, G, Chowdhury, T, J O’Sullivan, M, de Krijger, RR, Stratton, MR, Pritchard-Jones, K, Hutchinson, JC, Drost, J & Behjati, S 2025, 'High resolution clonal architecture of hypomutated Wilms tumours', Nature Communications, vol. 16, no. 1, 4647. https://doi.org/10.1038/s41467-025-59854-4

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T1 - High resolution clonal architecture of hypomutated Wilms tumours

AU - Lee-Six, Henry

AU - Treger, Taryn D.

AU - Dave, Manas

AU - Coorens, Tim H.H.

AU - Anderson, Nathaniel D.

AU - Tiersma, Yvonne

AU - Derakhshan, Sepide

AU - de Haan, Sanne

AU - van den Heuvel-Eibrink, Marry M.

AU - Wang, Yichen

AU - Wenger, Anna

AU - Al-Saadi, Reem

AU - Lawford, Alice

AU - Letunovska, Aleksandra

AU - Wegert, Jenny

AU - Parks, Conor

AU - Morcrette, Guillaume

AU - Gessler, Manfred

AU - Vujanic, Gordan

AU - Chowdhury, Tanzina

AU - J O’Sullivan, Maureen

AU - de Krijger, Ronald R.

AU - Stratton, Michael R.

AU - Pritchard-Jones, Kathy

AU - Hutchinson, J. Ciaran

AU - Drost, Jarno

AU - Behjati, Sam

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105006897669

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DO - 10.1038/s41467-025-59854-4

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AN - SCOPUS:105006897669

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4647

ER -

High resolution clonal architecture of hypomutated Wilms tumours

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