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Cancer Cell. 2015 Feb 9;27(2):298-311. doi: 10.1016/j.ccell.2015.01.002.

Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors.

Author information

1
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, 97074 Wuerzburg, Germany.
2
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
3
Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
4
Department of Pediatric Oncology and Hematology, Saarland University Hospital, 66421 Homburg, Germany.
5
Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
6
Theodor-Boveri-Institute/Biocenter, Biochemistry, Wuerzburg University, 97074 Wuerzburg, Germany.
7
Theodor-Boveri-Institute/Biocenter, Physiological Chemistry, Wuerzburg University, 97074 Wuerzburg, Germany.
8
UCL Institute of Child Health, London WC1N 1EH, UK.
9
Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
10
Unidad de Oncología Pediátrica, Hospital Materno-Infantil de Málaga, 29011 Malaga, Spain.
11
National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, and Trinity College, Dublin 12, Ireland.
12
Department of Pediatric Hematology and Oncology, Children's University Hospital, 8032 Zurich, Switzerland.
13
Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
14
Department of Pediatric Oncology, Erasmus MC-University Medical Center Rotterdam, 3000 CA Rotterdam, the Netherlands.
15
Kiel Paediatric Cancer Registry, Christian Albrechts University, 24105 Kiel, Germany.
16
Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, 69121 Heidelberg, Germany.
17
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
18
Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, 97074 Wuerzburg, Germany. Electronic address: gessler@biozentrum.uni-wuerzburg.de.

Abstract

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.

PMID:
25670083
DOI:
10.1016/j.ccell.2015.01.002
[Indexed for MEDLINE]
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