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Int J Cancer. 2019 Aug 15;145(4):941-951. doi: 10.1002/ijc.32167. Epub 2019 Feb 14.

TRIM28 haploinsufficiency predisposes to Wilms tumor.

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Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Institute of Human Genetics, Erlangen, Germany.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Department of Medical Biology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
Department of Pediatrics, Children's University Hospital, Comenius University, Bratislava, Slovakia.
Department for Health Evidence, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands.
Department of Pediatrics, Radboudumc Amalia's Children's Hospital, Nijmegen, The Netherlands.
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
Department of Pediatric Hematology and Oncology, Saarland University, Medical Center Homburg/Saar, Homburg, Germany.
Kiel Pediatric Tumor Registry, Section of Pediatric Pathology, Department of Pathology, Christian Albrechts University, Kiel, Germany.
Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.


Two percent of patients with Wilms tumors have a positive family history. In many of these cases the genetic cause remains unresolved. By applying germline exome sequencing in two families with two affected individuals with Wilms tumors, we identified truncating mutations in TRIM28. Subsequent mutational screening of germline and tumor DNA of 269 children affected by Wilms tumor was performed, and revealed seven additional individuals with germline truncating mutations, and one individual with a somatic truncating mutation in TRIM28. TRIM28 encodes a complex scaffold protein involved in many different processes, including gene silencing, DNA repair and maintenance of genomic integrity. Expression studies on mRNA and protein level showed reduction of TRIM28, confirming a loss-of-function effect of the mutations identified. The tumors showed an epithelial-type histology that stained negative for TRIM28 by immunohistochemistry. The tumors were bilateral in six patients, and 10/11 tumors are accompanied by perilobar nephrogenic rests. Exome sequencing on eight tumor DNA samples from six individuals showed loss-of-heterozygosity (LOH) of the TRIM28-locus by mitotic recombination in seven tumors, suggesting that TRIM28 functions as a tumor suppressor gene in Wilms tumor development. Additionally, the tumors showed very few mutations in known Wilms tumor driver genes, suggesting that loss of TRIM28 is the main driver of tumorigenesis. In conclusion, we identified heterozygous germline truncating mutations in TRIM28 in 11 children with mainly epithelial-type Wilms tumors, which become homozygous in tumor tissue. These data establish TRIM28 as a novel Wilms tumor predisposition gene, acting as a tumor suppressor gene by LOH.


TRIM28; Wilms tumor; genetic predisposition; haploinsufficiency


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