TRIM28 haploinsufficiency predisposes to Wilms tumor

Diets IJ, Hoyer J, Ekici AB, Popp B, Hoogerbrugge N, van Reijmersdal SV, Bhaskaran R, Hadjihannas M, Vasileiou G, Thiel C, Seven D, Uebe S, Ilencikova D, Waanders E, Mavinkurve-Groothuis AM, Roeleveld N, de Krijger RR, Wegert J, Graf N, Vokuhl C, Agaimy A, Gessler M, Reis A, Kuiper RP, Jongmans MC, Metzler M (2019)

Publication Type: Journal article

Publication year: 2019

Journal

International Journal of Cancer Wiley-Blackwell

DOI: 10.1002/ijc.32167

Abstract

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.

Authors with CRIS profile

Juliane Hoyer Institute of Human Genetics Arif Bülent Ekici Institute of Human Genetics Bernt Popp Institute of Human Genetics Michel Hadjihannas Institute of Human Genetics Christian Thiel Medizinische Fakultät Steffen Uebe Institute of Human Genetics Abbas Agaimy Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Markus Metzler Professur für Kinder- und Jugendmedizin mit dem Schwerpunkt Pädiatrische Onkologie und Hämatologie

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Princess Máxima Center NL Netherlands (NL) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Christian-Albrechts-Universität zu Kiel DE Germany (DE)

How to cite

APA:

Diets, I.J., Hoyer, J., Ekici, A.B., Popp, B., Hoogerbrugge, N., van Reijmersdal, S.V.,... Metzler, M. (2019). TRIM28 haploinsufficiency predisposes to Wilms tumor. International Journal of Cancer. https://dx.doi.org/10.1002/ijc.32167

MLA:

Diets, Illja J., et al. "TRIM28 haploinsufficiency predisposes to Wilms tumor." International Journal of Cancer (2019).

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