TRIM28 haploinsufficiency predisposes to Wilms tumor
| Autor: | Bernt Popp, Abbas Agaimy, Georgia Vasileiou, Marjolijn C.J. Jongmans, Illja J. Diets, Nel Roeleveld, Nicoline Hoogerbrugge, Markus Metzler, Denisa Ilencikova, Roland P. Kuiper, Annelies M. C. Mavinkurve-Groothuis, Didem Seven, Steffen Uebe, Arif B. Ekici, Jenny Wegert, Rajith Bhaskaran, Esmé Waanders, Manfred Gessler, Christian Thiel, Juliane Hoyer, Ronald R. de Krijger, André Reis, Norbert Graf, Simon V. van Reijmersdal, Christian Vokuhl, Michel V. Hadjihannas |
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| Přispěvatelé: | İÜC |
| Rok vydání: | 2019 |
| Předmět: |
Male
Haploinsufficiency/genetics Cancer Research Carcinogenesis Whole Exome Sequencing/methods lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Loss of Heterozygosity Haploinsufficiency Tripartite Motif-Containing Protein 28 medicine.disease_cause Germ-Line Mutation/genetics Kidney Neoplasms/genetics Germline Loss of Function Mutation/genetics 0302 clinical medicine Loss of Function Mutation Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] Child Non-U.S. Gov't Exome sequencing Genetic Predisposition to Disease/genetics Research Support Non-U.S. Gov't Wilms tumor Wilms Tumor/physiology DNA Neoplasm Kidney Neoplasms Oncology Child Preschool 030220 oncology & carcinogenesis Female Heterozygote Genes Wilms Tumor Mitotic crossover Genotype Tumor suppressor gene DNA repair Biology Research Support Wilms Tumor 03 medical and health sciences Exome Sequencing Journal Article medicine Humans Genetic Predisposition to Disease Preschool DNA Neoplasm/genetics Germ-Line Mutation Genes Wilms Tumor/physiology Neoplasm/genetics Loss of Heterozygosity/genetics TRIM28 Infant Wilms' tumor DNA medicine.disease haploinsufficiency Wilms Tumor/genetics Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] Genes Tripartite Motif-Containing Protein 28/genetics Cancer research Carcinogenesis/genetics genetic predisposition |
| Zdroj: | International Journal of Cancer, 145, 4, pp. 941-951 International Journal of Cancer, 145, 941-951 International Journal of Cancer, 145(4), 941. Wiley-Liss Inc. |
| ISSN: | 0020-7136 |
| DOI: | 10.1002/ijc.32167 |
| Popis: | Graf, Norbert/0000-0002-2248-323X; Reis, Andre/0000-0002-6301-6363; Diets, Illja/0000-0001-7603-8898; Popp, Bernt/0000-0002-3679-1081; Thiel, Christian T/0000-0003-3817-7277; Roeleveld, Nel/0000-0002-3390-4466; Reis, AlessanRSS/0000-0001-8486-7469; Vasileiou, Georgia/0000-0002-1993-1134; Gessler, Manfred/0000-0002-7915-6045 WOS:000472571300008 PubMed ID: 30694527 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. Dutch Cancer SocietyKWF Kankerbestrijding [KUN2012-5366]; KiKa Foundation [127] Grant sponsor: Dutch Cancer Society; Grant number: KUN2012-5366; Grant sponsor: The KiKa Foundation (project 127) |
| Databáze: | OpenAIRE |
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