Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors
Blastemal 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..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2015 |
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| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Cancer cell - 27(2015), 2, Seite 298-311 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wegert, Jenny [VerfasserIn] |
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| Links: |
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| doi: |
10.1016/j.ccell.2015.01.002 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors |
| 264 | 1 | |c 2015 | |
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| 520 | |a Blastemal 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. | ||
| 540 | |a Nutzungsrecht: Copyright © 2015 Elsevier Inc. All rights reserved. | ||
| 650 | 4 | |a Nerve Tissue Proteins - genetics | |
| 650 | 4 | |a Ribonuclease III - genetics | |
| 650 | 4 | |a Wilms Tumor - genetics | |
| 650 | 4 | |a RNA-Binding Proteins - genetics | |
| 650 | 4 | |a Wilms Tumor - pathology | |
| 650 | 4 | |a MicroRNAs - biosynthesis | |
| 650 | 4 | |a Neoplasm Proteins - biosynthesis | |
| 650 | 4 | |a Homeodomain Proteins - genetics | |
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| 700 | 1 | |a Bieg, Matthias |4 oth | |
| 700 | 1 | |a Ziegler, Barbara |4 oth | |
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| 700 | 1 | |a Nourkami, Nasenien |4 oth | |
| 700 | 1 | |a Ludwig, Nicole |4 oth | |
| 700 | 1 | |a Keller, Andreas |4 oth | |
| 700 | 1 | |a Grimm, Clemens |4 oth | |
| 700 | 1 | |a Kneitz, Susanne |4 oth | |
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