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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed 129 children with suspected Wilms tumor predisposition, 20 familial cases, and 109 children with bilateral disease, enrolled over 30\u00a0years 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>WT1<\/jats:italic>\n                      (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200935) and less frequently\n                      <jats:italic>TRIM28<\/jats:italic>\n                      ,\n                      <jats:italic>REST<\/jats:italic>\n                      ,\n                      <jats:italic>DIS3L2<\/jats:italic>\n                      ,\n                      <jats:italic>CTR9<\/jats:italic>\n                      ,\n                      <jats:italic>DICER1<\/jats:italic>\n                      ,\n                      <jats:italic>CDC73<\/jats:italic>\n                      , and\n                      <jats:italic>NONO<\/jats:italic>\n                      . Nine children carried germline mutations in cancer predisposition genes not considered Wilms tumor predisposition genes, such as\n                      <jats:italic>CHEK2<\/jats:italic>\n                      ,\n                      <jats:italic>CDKN2A<\/jats:italic>\n                      ,\n                      <jats:italic>BLM<\/jats:italic>\n                      ,\n                      <jats:italic>BRCA2<\/jats:italic>\n                      ,\n                      <jats:italic>STK11<\/jats:italic>\n                      , and\n                      <jats:italic>FMN2<\/jats:italic>\n                      .\n                    <\/jats:p>\n                    <jats:p>\n                      Predisposition via epigenetic BWS-IC1 alterations occurred as early somatic events, reflected by partial (mosaic) loss of imprinting or loss of heterozygosity at the\n                      <jats:italic>IGF2\/H19<\/jats:italic>\n                      locus in normal kidney or blood. These patients rarely had a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS).\n                    <\/jats:p>\n                    <jats:p>\n                      Especially\n                      <jats:italic>WT1-<\/jats:italic>\n                      driven tumors follow a stereotypical pathway of germline\n                      <jats:italic>WT1<\/jats:italic>\n                      mutations becoming homozygous in renal precursor lesions through 11p LOH, which concomitantly activates imprinted\n                      <jats:italic>IGF2<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>IGF2<\/jats:italic>\n                      . These findings inform future genetic screening and risk assessment of affected children and lend support to liquid biopsy screening for enhanced therapeutic stratification.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-025-01482-0","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T03:24:07Z","timestamp":1746674647000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor"],"prefix":"10.1186","volume":"17","author":[{"given":"Jenny","family":"Wegert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Appenzeller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taryn 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Informed consent had been obtained from all patients\/parents. All samples were pseudonymized. Biobank operation was approved by the Ethikkommission of the University of W\u00fcrzburg (reference 336\/21_z-sc). This research conforms to the principles of the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"49"}}