Predisposition Footprints in the Somatic Genome of Wilms Tumors

Approximately 10% of children with cancer harbor a mutation in a predisposition gene. In children with the kidney cancer Wilms tumor, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumorigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumor, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA sequencing, and genome-wide methylation, validating our findings in an independent cohort. Tumor development differed in children harboring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high-risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumorigenesis, suggesting a variant-specific approach to managing children merits consideration. Significance: Tumors that arise in children with a cancer predisposition may develop through the same mutational pathways as sporadic tumors. We examined this question in the childhood kidney cancer, Wilms tumor. We found that certain predispositions dictate the genetic development of tumors, with clinical implications for these children. See related commentary by Brzezinski and Malkin, p. 258.

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Publication Details

Journal
Cancer Discovery
Published
2024-12-12
DOI
https://doi.org/10.1158/2159-8290.cd-24-0878
Citations
10
Primary Topic
Renal and related cancers
Type
article
Field-Weighted Citation Impact
2.34

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article

Predisposition Footprints in the Somatic Genome of Wilms Tumors

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Predisposition Footprints in the Somatic Genome of Wilms Tumors

Hyunchul Jung, Mi K. Trinh, Jack Luke Bartram, Angus Hodder, Ruben van Boxtel, Evangelia Antoniou, Bianca F. Goemans, Guillaume Morcrette, Norbert M. Graf, Kathy Pritchard‐Jones, Marry M. van den Heuvel‐Eibrink, Henry Lee-Six, Reem Al‐Saadi, Jarno Drost, Rhoikos Furtwängler, Jenny Wegert, J. Ciaran Hutchinson, Tanzina Chowdhury, B Ziegler, Tim Coorens, Heike Streitenberger, Anna Wenger, Sam Behjati, Gordan Vujanić, Dirk Reinhardt, Paul G. Kemps, Taryn D. Treger, Manfred Gessler, Nathaniel D. Anderson, Eline J.M. Bertrums, Conor Parks, Aleksandra Letunovska, Jonathan Kennedy, Toochi Ogbonnah, Christian Vokuhl
article en
10 citations

Abstract

Approximately 10% of children with cancer harbor a mutation in a predisposition gene. In children with the kidney cancer Wilms tumor, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumorigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumor, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukemias), utilizing whole-genome sequencing, RNA sequencing, and genome-wide methylation, validating our findings in an independent cohort. Tumor development differed in children harboring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high-risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumorigenesis, suggesting a variant-specific approach to managing children merits consideration. Significance: Tumors that arise in children with a cancer predisposition may develop through the same mutational pathways as sporadic tumors. We examined this question in the childhood kidney cancer, Wilms tumor. We found that certain predispositions dictate the genetic development of tumors, with clinical implications for these children. See related commentary by Brzezinski and Malkin, p. 258.

Cancer DiscoveryVol. 15(2)
Broad Institute (US), Qatar Airways (Qatar) (QA), University of Bonn (DE), Inserm (FR), Université Paris Cité (FR), University of Cambridge (GB), University of Würzburg (DE), University Hospital Bonn (DE), Great Ormond Street Hospital (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Hospital for Sick Children (CA), Cambridge University Hospitals NHS Foundation Trust (GB), Wellcome Sanger Institute (GB), Christian-Albrechts-Universität zu Kiel (DE), Assistance Publique – Hôpitaux de Paris (FR), Comprehensive Cancer Center Mainfranken (DE), Netherlands Heart Institute (NL), Essen University Hospital (DE), University Children’s Hospital Bern (CH), Princess Máxima Center (NL), Berufsförderungszentrum Essen (DE), University College London (GB), Saarland University (DE)
Wilhelm Sander-Stiftung, Wellcome Trust, Wenner-Gren Stiftelserna, National Institute for Health and Care Research, University of Cambridge, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Little Princess Trust, NIHR Cambridge Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre
Life below water
Openalex Percentile: Top 11%
Renal and related cancers
2.34
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