title: Wilms tumor gene 1 (WT1), TP53, RAS/BRAF and KIT aberrations in testicular germ cell tumors.
abstract: Wilms tumor gene 1 (WT1), a zinc-finger transcription factor essential for testis development and function, along with other genes, was investigated for their role in the pathogenesis of testicular germ cell tumors (TGCT).
  
  
  
  In total, 284 TGCT and 100 control samples were investigated, including qPCR for WT1 expression and BRAF mutation, p53 immunohistochemistry detection, and massively parallel amplicon sequencing.
  
  
  
  WT1 was significantly (p < 0.0001) under-expressed in TGCT, with an increased ratio of exon 5-lacking isoforms, reaching low levels in chemo-naïve relapsed TGCT patients vs. high levels in chemotherapy-pretreated relapsed patients. BRAF V600E mutation was identified in 1% of patients only. p53 protein was lowly expressed in TGCT metastases compared to the matched primary tumors. Of 9 selected TGCT-linked genes, RAS/BRAF and WT1 mutations were frequent while significant TP53 and KIT variants were not detected (p = 0.0003).
  
  
  
  WT1 has been identified as a novel factor involved in TGCT pathogenesis, with a potential prognostic impact. Distinct biologic nature of the two types of relapses occurring in TGCT has been demonstrated. Differential mutation rate of the key TGCT-related genes has been documented.
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. Electronic address: ludmila.boublikova@lfmotol.cuni.cz.
authors.forename: L
authors.initials: L
authors.lastname: Boublikova
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Bakardjieva-Mihaylova
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Skvarova Kramarzova
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: D
authors.initials: D
authors.lastname: Kuzilkova
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: A
authors.initials: A
authors.lastname: Dobiasova
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: K
authors.initials: K
authors.lastname: Fiser
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Stuchly
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Kotrova
authors.affiliation: Department of Oncology, 1st Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic.
authors.forename: T
authors.initials: T
authors.lastname: Buchler
authors.affiliation: Department of Urology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Dusek
authors.affiliation: Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Grega
authors.affiliation: Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic.
authors.forename: B
authors.initials: B
authors.lastname: Rosova
authors.affiliation: Department of Pathology, 3rd Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic.
authors.forename: Z
authors.initials: Z
authors.lastname: Vernerova
authors.affiliation: Department of Urology, 3rd Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Klezl
authors.affiliation: Department of Urology, 1st Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Pesl
authors.affiliation: Department of Urology, Thomayer Hospital, Prague, Czech Republic.
authors.forename: R
authors.initials: R
authors.lastname: Zachoval
authors.affiliation: Department of Urology, Na Bulovce Hospital, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Krolupper
authors.affiliation: Department of Oncology and Radiotherapy, 3rd Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Kubecova
authors.affiliation: Institute of Radiotherapy and Oncology, 1st Faculty of Medicine, Charles University and Na Bulovce Hospital, Prague, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Stahalova
authors.affiliation: Department of Oncology, 1st Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Abrahamova
authors.affiliation: Department of Urology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Babjuk
authors.affiliation: Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: R
authors.initials: R
authors.lastname: Kodet
authors.affiliation: Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Trka
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis / Q000379:methods; D015536:Down-Regulation; D005240:Feasibility Studies; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009373:Neoplasms, Germ Cell and Embryonal / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D013736:Testicular Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025721:WT1 Proteins; C583751:WT1 protein, human; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: KIT; Next generation sequencing; TP53; Testicular germ cell tumors; Wilms tumor gene 1 (WT1)