title: Mutations in the SIX1/2 pathway and the DROSHA/DGCR8 miRNA microprocessor complex underlie high-risk blastemal type Wilms tumors.
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.
authors: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, 97074 Wuerzburg, Germany.
authors: Jenny
authors: J
authors: Wegert
authors: 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.
authors: Naveed
authors: N
authors: Ishaque
authors: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, 97074 Wuerzburg, Germany.
authors: Romina
authors: R
authors: Vardapour
authors: Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors: Christina
authors: C
authors: Geörg
authors: 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.
authors: Zuguang
authors: Z
authors: Gu
authors: 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.
authors: Matthias
authors: M
authors: Bieg
authors: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, 97074 Wuerzburg, Germany.
authors: Barbara
authors: B
authors: Ziegler
authors: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, 97074 Wuerzburg, Germany.
authors: Sabrina
authors: S
authors: Bausenwein
authors: Department of Pediatric Oncology and Hematology, Saarland University Hospital, 66421 Homburg, Germany.
authors: Nasenien
authors: N
authors: Nourkami
authors: Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
authors: Nicole
authors: N
authors: Ludwig
authors: Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
authors: Andreas
authors: A
authors: Keller
authors: Theodor-Boveri-Institute/Biocenter, Biochemistry, Wuerzburg University, 97074 Wuerzburg, Germany.
authors: Clemens
authors: C
authors: Grimm
authors: Theodor-Boveri-Institute/Biocenter, Physiological Chemistry, Wuerzburg University, 97074 Wuerzburg, Germany.
authors: Susanne
authors: S
authors: Kneitz
authors: UCL Institute of Child Health, London WC1N 1EH, UK.
authors: Richard D
authors: RD
authors: Williams
authors: UCL Institute of Child Health, London WC1N 1EH, UK.
authors: Tas
authors: T
authors: Chagtai
authors: UCL Institute of Child Health, London WC1N 1EH, UK.
authors: Kathy
authors: K
authors: Pritchard-Jones
authors: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
authors: Peter
authors: P
authors: van Sluis
authors: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
authors: Richard
authors: R
authors: Volckmann
authors: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
authors: Jan
authors: J
authors: Koster
authors: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
authors: Rogier
authors: R
authors: Versteeg
authors: Unidad de Oncología Pediátrica, Hospital Materno-Infantil de Málaga, 29011 Malaga, Spain.
authors: Tomas
authors: T
authors: Acha
authors: National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, and Trinity College, Dublin 12, Ireland.
authors: Maureen J
authors: MJ
authors: O'Sullivan
authors: Department of Pediatric Hematology and Oncology, Children's University Hospital, 8032 Zurich, Switzerland.
authors: Peter K
authors: PK
authors: Bode
authors: Department of Pediatric Hematology and Oncology, Children's University Hospital, 8032 Zurich, Switzerland.
authors: Felix
authors: F
authors: Niggli
authors: Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
authors: Godelieve A
authors: GA
authors: Tytgat
authors: Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, the Netherlands.
authors: Harm
authors: H
authors: van Tinteren
authors: Department of Pediatric Oncology, Erasmus MC-University Medical Center Rotterdam, 3000 CA Rotterdam, the Netherlands.
authors: Marry M
authors: MM
authors: van den Heuvel-Eibrink
authors: Department of Human Genetics, Saarland University, 66421 Homburg, Germany.
authors: Eckart
authors: E
authors: Meese
authors: Kiel Paediatric Cancer Registry, Christian Albrechts University, 24105 Kiel, Germany.
authors: Christian
authors: C
authors: Vokuhl
authors: Kiel Paediatric Cancer Registry, Christian Albrechts University, 24105 Kiel, Germany.
authors: Ivo
authors: I
authors: Leuschner
authors: Department of Pediatric Oncology and Hematology, Saarland University Hospital, 66421 Homburg, Germany.
authors: Norbert
authors: N
authors: Graf
authors: 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.
authors: Roland
authors: R
authors: Eils
authors: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Stefan M
authors: SM
authors: Pfister
authors: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Marcel
authors: M
authors: Kool
authors: Theodor-Boveri-Institute/Biocenter, Developmental Biochemistry, and Comprehensive Cancer Center Mainfranken, Wuerzburg University, 97074 Wuerzburg, Germany. Electronic address: gessler@biozentrum.uni-wuerzburg.de.
authors: Manfred
authors: M
authors: Gessler
mesh_terms: D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics*; D059467:Transcriptome; D009396:Wilms Tumor / Q000235:genetics* / Q000473:pathology
chemical_list: C474043:DGCR8 protein, human; D018398:Homeodomain Proteins; D035683:MicroRNAs; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C099236:SIX1 protein, human; C484762:SIX2 protein, human; C517918:DROSHA protein, human; D043244:Ribonuclease III