{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:40:42Z","timestamp":1792039242488,"version":"4.4.0"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Ge539\/14"],"award-info":[{"award-number":["Ge539\/14"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005972","name":"Deutsche Krebshilfe","doi-asserted-by":"publisher","award":["50\u20102709\u2010Gr2"],"award-info":[{"award-number":["50\u20102709\u2010Gr2"]}],"id":[{"id":"10.13039\/501100005972","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022850","name":"Little Princess Trust","doi-asserted-by":"publisher","award":["CCLGA 2019 27"],"award-info":[{"award-number":["CCLGA 2019 27"]}],"id":[{"id":"10.13039\/501100022850","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite\u2010motif\u2010containing\u201028 gene (\n                    <jats:italic>TRIM28<\/jats:italic>\n                    ). Case reports and small case series suggest that\n                    <jats:italic>TRIM28<\/jats:italic>\n                    mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of\n                    <jats:italic>TRIM28<\/jats:italic>\n                    inactivation and predisposing mutations in a cohort of 126 WTs with &gt;2\/3 epithelial cells, spanning 20\u2009years of biobanking in the German SIOP93\u201001\/GPOH and SIOP2001\/GPOH studies. Overall, 44.4% (56\/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing\n                    <jats:italic>TRIM28<\/jats:italic>\n                    sequence variants in each case \u2013 either homozygous (~2\/3) or heterozygous with epigenetic silencing of the second allele (~1\/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc\u2010binding clusters of the RING, B\u2010box\u20102, and PHD domains or the central coiled\u2010coil region.\n                    <jats:italic>TRIM28\u2010<\/jats:italic>\n                    mutant tumors otherwise lacked WT\u2010typical\n                    <jats:italic>IGF2<\/jats:italic>\n                    alterations or driver events, except for rare\n                    <jats:italic>TP53<\/jats:italic>\n                    progression events that occurred with expected frequency. Expression profiling identified\n                    <jats:italic>TRIM28\u2010<\/jats:italic>\n                    mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic\n                    <jats:italic>TRIM28<\/jats:italic>\n                    alterations in 7\/7 cases tested. Importantly, 46% of the\n                    <jats:italic>TRIM28<\/jats:italic>\n                    mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in\n                    <jats:italic>TRIM28\u2010<\/jats:italic>\n                    driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. \u00a9 2023 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6206","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T13:01:44Z","timestamp":1696424504000},"page":"10-21","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["<scp>\n                      <i>TRIM28<\/i>\n                    <\/scp>\n                    inactivation in epithelial nephroblastoma is frequent and often associated with predisposing\n                    <scp>\n                      <i>TRIM28<\/i>\n                    <\/scp>\n                    germline variants"],"prefix":"10.1002","volume":"262","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4505-5519","authenticated-orcid":false,"given":"Jenny","family":"Wegert","sequence":"first","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Developmental Biochemistry University of Wuerzburg  Wuerzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Kristin","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balazs","family":"Palhazi","sequence":"additional","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Developmental Biochemistry University of Wuerzburg  Wuerzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taryn D","family":"Treger","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute  Hinxton UK"},{"name":"Department of Paediatrics University of Cambridge  Cambridge UK"},{"name":"Cambridge University Hospitals NHS Foundation Trust  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e4cilia","family":"Hilgers","sequence":"additional","affiliation":[{"name":"Department of Pathology, Section of Pediatric Pathology University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Developmental Biochemistry University of Wuerzburg  Wuerzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunchul","family":"Jung","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute  Hinxton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"J\u00fcttner","sequence":"additional","affiliation":[{"name":"Department of Pathology Schleswig\u2010Holstein University Hospital  Kiel Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Waha","sequence":"additional","affiliation":[{"name":"Department of Neuropathology University of Bonn  Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery and Pediatric Urology University Children's Hospital T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven W","family":"Warmann","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery and Pediatric Urology University Children's Hospital T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C","family":"Fr\u00fchwald","sequence":"additional","affiliation":[{"name":"Swabian Children's Cancer Center, Pediatrics and Adolescent Medicine University Hospital Augsburg  Augsburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Hubertus","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery at Marienhospital Witten Ruhr\u2010University Bochum  Witten Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Pritchard\u2010Jones","sequence":"additional","affiliation":[{"name":"UCL Great Ormond Street Institute of Child Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2248-323X","authenticated-orcid":false,"given":"Norbert","family":"Graf","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology and Oncology Saarland University Hospital  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Behjati","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute  Hinxton UK"},{"name":"Department of Paediatrics University of Cambridge  Cambridge UK"},{"name":"Cambridge University Hospitals NHS Foundation Trust  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhoikos","family":"Furtw\u00e4ngler","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology and Oncology Saarland University Hospital  Homburg Germany"},{"name":"Pediatric Hematology and Oncology Inselspital Children's Hospital, University Bern  Bern Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7915-6045","authenticated-orcid":false,"given":"Manfred","family":"Gessler","sequence":"additional","affiliation":[{"name":"Theodor\u2010Boveri\u2010Institute\/Biocenter, Developmental Biochemistry University of Wuerzburg  Wuerzburg Germany"},{"name":"Comprehensive Cancer Center Mainfranken University of Wuerzburg  Wuerzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Vokuhl","sequence":"additional","affiliation":[{"name":"Department of Pathology, Section of Pediatric Pathology University of Bonn  Bonn 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