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Titel: TRIM28 haploinsufficiency predisposes to Wilms tumor
VerfasserIn: Diets, Illja J.
Hoyer, Juliane
Ekici, Arif B.
Popp, Bernt
Hoogerbrugge, Nicoline
van 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
de Krijger, Ronald R.
Wegert, Jenny
Graf, Norbert
Vokuhl, Christian
Agaimy, Abbas
Gessler, Manfred
Reis, André
Kuiper, Roland P.
Jongmans, Marjolijn C. J.
Metzler, Markus
Sprache: Englisch
Titel: International Journal of Cancer
Bandnummer: 145
Heft: 4
Seiten: 941-951
Verlag/Plattform: Wiley
Erscheinungsjahr: 2019
Freie Schlagwörter: Wilms tumor
haploinsufficiency
TRIM28
genetic predisposition
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
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.
DOI der Erstveröffentlichung: 10.1002/ijc.32167
URL der Erstveröffentlichung: https://doi.org/10.1002/ijc.32167
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-410310
hdl:20.500.11880/36822
http://dx.doi.org/10.22028/D291-41031
ISSN: 1097-0215
0020-7136
Datum des Eintrags: 10-Nov-2023
Bezeichnung des in Beziehung stehenden Objekts: Supporting Information
In Beziehung stehendes Objekt: https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fijc.32167&file=ijc32167-sup-0001-supinfo.pdf
https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fijc.32167&file=ijc32167-sup-0002-Tables.xlsx
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Pädiatrie
Professur: M - Prof. Dr. Norbert Graf
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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