TRIM28 haploinsufficiency predisposes to Wilms tumor

Illja J Diets, Juliane Hoyer, Arif B Ekici, Bernt Popp, Nicoline Hoogerbrugge, Simon V van Reijmersdal, Rajith Bhaskaran, Michel Hadjihannas, Georgia Vasileiou, Christian T Thiel, Didem Seven, Steffen Uebe, Denisa Ilencikova, Esmé Waanders, Annelies M C Mavinkurve-Groothuis, Nel Roeleveld, Ronald R de Krijger, Jenny Wegert, Norbert Graf, Christian VokuhlAbbas Agaimy, Manfred Gessler, André Reis, Roland Kuiper, Marjolijn C J Jongmans, Markus Metzler

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)941-951
Aantal pagina's11
TijdschriftInternational journal of cancer
Volume145
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 15 aug. 2019

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