Wegert, Jenny and Appenzeller, Silke and Treger, Taryn D. and Streitenberger, Heike and Ziegler, Barbara and Bausenwein, Sabrina and Vokuhl, Christian and Parks, Conor and Juettner, Eva and Gramlich, Susanne and Ernestus, Karen and Warman, Steven W. and Fuchs, Joerg and Hubertus, Jochen and von Schweinitz, Dietrich and Froehlich, Birgit and Jorch, Norbert and Knoefler, Ralf and Friedrich, Carsten and Corbacioglu, Selim and Fruehwald, Michael C. and Pekrun, Arnulf and Schneider, Dominik T. and Faber, Joerg and Stursberg, Jana and Metzler, Markus and Welter, Nils and Pritchard-Jones, Kathy and Graf, Norbert and Furtwaengler, Rhoikos and Behjati, Sam and Gessler, Manfred (2025) Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor. GENOME MEDICINE, 17 (1): 49. ISSN 1756-994X,
Full text not available from this repository. (Request a copy)Abstract
BackgroundGenetic 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.MethodsWe 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.ResultsPredisposing 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.ResultsPredisposing 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. ResultsPredisposing 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.ConclusionsWe 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BECKWITH-WIEDEMANN SYNDROME; GERMLINE MUTATIONS; PERLMAN SYNDROME; CANCER; RISK; SUSCEPTIBILITY; RELAXATION; GENOME; DIS3L2; Wilms tumor; Nephroblastoma; Genomic imprinting; Hereditary cancer; Cancer predisposition; Pediatric cancer; Multicentric tumors; WT1; BWS |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 31 Mar 2026 12:02 |
| Last Modified: | 31 Mar 2026 12:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67800 |
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