Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor
Abstract Background Genetic predisposition is particularly common in children with the kidney cancer, Wilms tumor. In 10% of these children, this manifests as a family history of Wilms tumor or bilateral disease. The frequency and spectrum of underlying changes have not been systematically investiga...
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2025-05-01
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| author | Jenny Wegert Silke Appenzeller Taryn D. Treger Heike Streitenberger Barbara Ziegler Sabrina Bausenwein Christian Vokuhl Conor Parks Eva Jüttner Susanne Gramlich Karen Ernestus Steven W. Warman Jörg Fuchs Jochen Hubertus Dietrich von Schweinitz Birgit Fröhlich Norbert Jorch Ralf Knöfler Carsten Friedrich Selim Corbacioglu Michael C. Frühwald Arnulf Pekrun Dominik T. Schneider Jörg Faber Jana Stursberg Markus Metzler Nils Welter Kathy Pritchard-Jones Norbert Graf Rhoikos Furtwängler Sam Behjati Manfred Gessler |
| author_facet | Jenny Wegert Silke Appenzeller Taryn D. Treger Heike Streitenberger Barbara Ziegler Sabrina Bausenwein Christian Vokuhl Conor Parks Eva Jüttner Susanne Gramlich Karen Ernestus Steven W. Warman Jörg Fuchs Jochen Hubertus Dietrich von Schweinitz Birgit Fröhlich Norbert Jorch Ralf Knöfler Carsten Friedrich Selim Corbacioglu Michael C. Frühwald Arnulf Pekrun Dominik T. Schneider Jörg Faber Jana Stursberg Markus Metzler Nils Welter Kathy Pritchard-Jones Norbert Graf Rhoikos Furtwängler Sam Behjati Manfred Gessler |
| author_sort | Jenny Wegert |
| collection | DOAJ |
| description | Abstract Background Genetic predisposition is particularly common in children with the kidney cancer, Wilms tumor. In 10% of these children, this manifests as a family history of Wilms tumor or bilateral disease. The frequency and spectrum of underlying changes have not been systematically investigated. Methods We analyzed 129 children with suspected Wilms tumor predisposition, 20 familial cases, and 109 children with bilateral disease, enrolled over 30 years in the German SIOP93-01/GPOH and SIOP2001 studies. We used whole exome, whole genome, and targeted DNA sequencing, together with MLPA and targeted methylation assays on tumor, blood, and normal kidney to determine predisposing changes. Results Predisposing variants were identified in 117/129 children, comprising DNA variants (57%) and epigenetic changes (34%). Most children had predisposition variants in genes previously implicated in Wilms tumor: most prominently WT1 (n = 35) and less frequently TRIM28, REST, DIS3L2, CTR9, DICER1, CDC73, and NONO. Nine children carried germline mutations in cancer predisposition genes not considered Wilms tumor predisposition genes, such as CHEK2, CDKN2A, BLM, BRCA2, STK11, and FMN2. Predisposition via epigenetic BWS-IC1 alterations occurred as early somatic events, reflected by partial (mosaic) loss of imprinting or loss of heterozygosity at the IGF2/H19 locus in normal kidney or blood. These patients rarely had a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS). Especially WT1-driven tumors follow a stereotypical pathway of germline WT1 mutations becoming homozygous in renal precursor lesions through 11p LOH, which concomitantly activates imprinted IGF2 expression, with subsequent WNT pathway activation leading to tumor growth. There is a high rate of multicentric tumors, which may have previously been missed in unilateral tumors. While Wilms tumor predisposition genes relied on somatic inactivation of the second allele, this was different for general cancer predisposition genes. The latter cases were often associated with additional oncogenic alterations, similar to tumors with epigenetic predisposition. Conclusions We identified two main mechanisms of Wilms tumor predisposition: either germline genetic alterations of Wilms tumor and, less frequently, general cancer genes; or postzygotic mosaic imprinting defects activating IGF2. These findings inform future genetic screening and risk assessment of affected children and lend support to liquid biopsy screening for enhanced therapeutic stratification. |
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| issn | 1756-994X |
| language | English |
| publishDate | 2025-05-01 |
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| series | Genome Medicine |
| spelling | doaj-art-7da05500cd424d2a95a090da5aaaafec2025-08-20T02:15:07ZengBMCGenome Medicine1756-994X2025-05-0117111510.1186/s13073-025-01482-0Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumorJenny Wegert0Silke Appenzeller1Taryn D. Treger2Heike Streitenberger3Barbara Ziegler4Sabrina Bausenwein5Christian Vokuhl6Conor Parks7Eva Jüttner8Susanne Gramlich9Karen Ernestus10Steven W. Warman11Jörg Fuchs12Jochen Hubertus13Dietrich von Schweinitz14Birgit Fröhlich15Norbert Jorch16Ralf Knöfler17Carsten Friedrich18Selim Corbacioglu19Michael C. Frühwald20Arnulf Pekrun21Dominik T. Schneider22Jörg Faber23Jana Stursberg24Markus Metzler25Nils Welter26Kathy Pritchard-Jones27Norbert Graf28Rhoikos Furtwängler29Sam Behjati30Manfred Gessler31Developmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Julius-Maximilians-University WürzburgComprehensive Cancer Center Mainfranken, University Hospital of WürzburgWellcome Sanger InstituteDevelopmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Julius-Maximilians-University WürzburgDevelopmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Julius-Maximilians-University WürzburgDevelopmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Julius-Maximilians-University WürzburgSection of Pediatric Pathology, Department of Pathology, University Hospital BonnWellcome Sanger InstituteDepartment of Pathology, Schleswig-Holstein University HospitalDepartment of Pathology, University of WürzburgDepartment of Pathology, University of WürzburgClinic of Pediatric Surgery, Charité – University Hospital BerlinDepartment of Pediatric Surgery and Pediatric Urology, University Children’s HospitalDepartment of Pediatric Surgery, Marien Hospital Witten, Ruhr-University BochumDepartment of Pediatric Surgery, Dr. von Hauner Children’s Hospital, LMU University HospitalDepartment of Pediatric Oncology and Hematology, University of MünsterEvangelisches Klinikum Bethel, Universitätsklinikum OWLDepartment of Pediatric Hematology/Oncology, Medizinische Fakultät Carl Gustav Carus, Technische Universität DresdenDepartment of Pediatrics and Pediatric Hematology/Oncology, University Children’s Hospital, Carl von Ossietzky UniversityChildren’s Hospital Regensburg, University of RegensburgSwabian Children’s Cancer Center, Pediatrics and Adolescent Medicine, University Hospital AugsburgPediatric Hematology and OncologyClinic of Pediatrics, University Witten/HerdeckeDepartment of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-UniversityDepartment of Pediatrics and Adolescent Medicine, Ulm University Medical CenterDepartment of Pediatrics and Adolescent Medicine, University of Erlangen-NürnbergDepartment of Pediatric Hematology and Oncology, Saarland University HospitalUCL Great Ormond Street Institute of Child Health, University College LondonDepartment of Pediatric Hematology and Oncology, Saarland University HospitalDepartment of Pediatric Hematology and Oncology, Saarland University HospitalWellcome Sanger InstituteDevelopmental Biochemistry, Theodor-Boveri-Institute/Biocenter, Julius-Maximilians-University WürzburgAbstract Background Genetic predisposition is particularly common in children with the kidney cancer, Wilms tumor. In 10% of these children, this manifests as a family history of Wilms tumor or bilateral disease. The frequency and spectrum of underlying changes have not been systematically investigated. Methods We analyzed 129 children with suspected Wilms tumor predisposition, 20 familial cases, and 109 children with bilateral disease, enrolled over 30 years in the German SIOP93-01/GPOH and SIOP2001 studies. We used whole exome, whole genome, and targeted DNA sequencing, together with MLPA and targeted methylation assays on tumor, blood, and normal kidney to determine predisposing changes. Results Predisposing variants were identified in 117/129 children, comprising DNA variants (57%) and epigenetic changes (34%). Most children had predisposition variants in genes previously implicated in Wilms tumor: most prominently WT1 (n = 35) and less frequently TRIM28, REST, DIS3L2, CTR9, DICER1, CDC73, and NONO. Nine children carried germline mutations in cancer predisposition genes not considered Wilms tumor predisposition genes, such as CHEK2, CDKN2A, BLM, BRCA2, STK11, and FMN2. Predisposition via epigenetic BWS-IC1 alterations occurred as early somatic events, reflected by partial (mosaic) loss of imprinting or loss of heterozygosity at the IGF2/H19 locus in normal kidney or blood. These patients rarely had a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS). Especially WT1-driven tumors follow a stereotypical pathway of germline WT1 mutations becoming homozygous in renal precursor lesions through 11p LOH, which concomitantly activates imprinted IGF2 expression, with subsequent WNT pathway activation leading to tumor growth. There is a high rate of multicentric tumors, which may have previously been missed in unilateral tumors. While Wilms tumor predisposition genes relied on somatic inactivation of the second allele, this was different for general cancer predisposition genes. The latter cases were often associated with additional oncogenic alterations, similar to tumors with epigenetic predisposition. Conclusions We identified two main mechanisms of Wilms tumor predisposition: either germline genetic alterations of Wilms tumor and, less frequently, general cancer genes; or postzygotic mosaic imprinting defects activating IGF2. These findings inform future genetic screening and risk assessment of affected children and lend support to liquid biopsy screening for enhanced therapeutic stratification.https://doi.org/10.1186/s13073-025-01482-0Wilms tumorNephroblastomaGenomic imprintingHereditary cancerCancer predispositionPediatric cancer |
| spellingShingle | Jenny Wegert Silke Appenzeller Taryn D. Treger Heike Streitenberger Barbara Ziegler Sabrina Bausenwein Christian Vokuhl Conor Parks Eva Jüttner Susanne Gramlich Karen Ernestus Steven W. Warman Jörg Fuchs Jochen Hubertus Dietrich von Schweinitz Birgit Fröhlich Norbert Jorch Ralf Knöfler Carsten Friedrich Selim Corbacioglu Michael C. Frühwald Arnulf Pekrun Dominik T. Schneider Jörg Faber Jana Stursberg Markus Metzler Nils Welter Kathy Pritchard-Jones Norbert Graf Rhoikos Furtwängler Sam Behjati Manfred Gessler Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor Genome Medicine Wilms tumor Nephroblastoma Genomic imprinting Hereditary cancer Cancer predisposition Pediatric cancer |
| title | Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor |
| title_full | Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor |
| title_fullStr | Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor |
| title_full_unstemmed | Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor |
| title_short | Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor |
| title_sort | distinct pathways for genetic and epigenetic predisposition in familial and bilateral wilms tumor |
| topic | Wilms tumor Nephroblastoma Genomic imprinting Hereditary cancer Cancer predisposition Pediatric cancer |
| url | https://doi.org/10.1186/s13073-025-01482-0 |
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