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Diets, Illja J.; Hoyer, Juliane; Ekici, Arif B.; Popp, Bernt; Hoogerbrugge, Nicoline; Reijmersdal, Simon V.; Bhaskaran, Rajith; Hadjihannas, Michel; Vasileiou, Georgia; Thiel, Christian T.; Seven, Didem; Uebe, Steffen; Ilencikova, Denisa; Waanders, Esmé; Mavinkurve‐Groothuis, Annelies M.C.; Roeleveld, Nel; Krijger, Ronald R.; Wegert, Jenny; Graf, Norbert; Vokuhl, Christian; Agaimy, Abbas; Gessler, Manfred; Reis, André; Kuiper, Roland P.; Jongmans, Marjolijn C.J.; Metzler, Markus
International journal of cancer, 15 August 2019, Volume: 145, Issue: 4Journal Article
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. What's new? About 2% of Wilms tumors run in families, and some of the mutations remain unknown. These authors identified a new Wilms tumor mutation, a truncation on the TRIM28 gene. They started by performing exome sequencing on tumors in pairs of affected children from 2 families. In these 4 patients, they found mutations in TRIM28, which encodes a scaffold protein involved in DNA repair and genome stability. They then screened a cohort of 269 cases and found 8 more patients bearing TRIM28 loss‐of‐function mutations. The gene appears to function as a tumor suppressor with loss of heterozygosity in the tumor cells.
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