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TRIM28 haploinsufficiency predisposes to Wilms tumor
Author(s) -
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,
MavinkurveGroothuis 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
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32167
Subject(s) - wilms' tumor , biology , loss of heterozygosity , haploinsufficiency , germline , carcinogenesis , germline mutation , cancer research , tumor suppressor gene , genetics , mutation , gene , allele , phenotype
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.