Mutations in the SIX1/2 Pathway and the DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal Type Wilms Tumors
| Autor: | Harm van Tinteren, Marry M. van den Heuvel-Eibrink, Barbara Ziegler, Peter K. Bode, Matthias Bieg, Ivo Leuschner, Felix Niggli, Marcel Kool, Jenny Wegert, Norbert Graf, Clemens Grimm, Zuguang Gu, Jan Koster, Richard D. Williams, Godelieve A.M. Tytgat, Eckart Meese, Kathy Pritchard-Jones, Sabrina Bausenwein, Tasnim Chagtai, Nicole Ludwig, Susanne Kneitz, Manfred Gessler, Naveed Ishaque, Christina Geörg, Christian Vokuhl, T Acha, Roland Eils, N. Nourkami, Romina Vardapour, Andreas Keller, Maureen J. O'Sullivan, Rogier Versteeg, Stefan M. Pfister, Peter van Sluis, Richard Volckmann |
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| Přispěvatelé: | Pediatrics, Pulmonary Medicine, Oncogenomics, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Paediatric Oncology, Other departments, University of Zurich, Gessler, Manfred |
| Rok vydání: | 2015 |
| Předmět: |
Ribonuclease III
Cancer Research DGCR8 610 Medicine & health Nerve Tissue Proteins medicine.disease_cause Wilms Tumor 1307 Cell Biology Microprocessor complex Transcriptome 10049 Institute of Pathology and Molecular Pathology microRNA medicine Humans 1306 Cancer Research Exome Drosha Homeodomain Proteins Mutation biology RNA-Binding Proteins Cancer Cell Biology medicine.disease Neoplasm Proteins Gene Expression Regulation Neoplastic MicroRNAs Oncology 10036 Medical Clinic biology.protein Cancer research 2730 Oncology |
| Zdroj: | Cancer Cell, 27(2), 298-311. Cell Press Cancer cell, 27(2), 298-311. Cell Press |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccell.2015.01.002 |
| Popis: | SummaryBlastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find therapeutic leads for this subgroup, we analyzed 58 blastemal type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large replication cohort. Recurrent mutations included a hotspot mutation (Q177R) in the homeo-domain of SIX1 and SIX2 in tumors with high proliferative potential (18.1% of blastemal cases); mutations in the DROSHA/DGCR8 microprocessor genes (18.2% of blastemal cases); mutations in DICER1 and DIS3L2; and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations strongly altered miRNA expression patterns in tumors, which was functionally validated in cell lines expressing mutant DROSHA. |
| Databáze: | OpenAIRE |
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