Mutations in the SIX1/2 Pathway and the DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal Type Wilms Tumors

• DOI: 10.1016/j.ccell.2015.01.002
• Publication Date: 2015-02-09T12:00:22Z
• Authors: Jenny Wegert; Naveed Ishaque; Romina Vardapour; Christina Geörg; Zuguang Gu; Matthias Bieg; Barbara Ziegler; Sabrina Bausenwein; Nasenien Nourkami; Nicole Ludwig; Andreas Keller; Clemens Grimm; Susanne Kneitz; Richard D. Williams; Tas Chagtai; Kathy Pritchard-J...; Peter van Sluis; Richard Volckmann; Jan Koster; Rogier Versteeg; Tomas Acha; Maureen J. O’Sull...; Peter K. Bode; Felix Niggli; Godelieve A. Tytgat; Harm van Tinteren; Marry M. van den ...; Eckart Meese; Christian Vokuhl; Ivo Leuschner; Norbert Graf; Roland Eils; Stefan M. Pfister; Marcel Kool; Manfred Gessler
• Keywords: Homeodomain Proteins; Ribonuclease III; 0301 basic medicine; Cancer Research; RNA-Binding Proteins; 610 Medicine & health; Nerve Tissue Proteins; Cell Biology; EMC MM-02-54-03; Wilms Tumor; Neoplasm Proteins; 3. Good health; 1307 Cell Biology; Gene Expression Regulation, Neoplastic; MicroRNAs; 03 medical and health sciences; Oncology; 10036 Medical Clinic; 10049 Institute of Pathology and Molecular Pathology; Mutation; Humans; 2730 Oncology; 1306 Cancer Research; Transcriptome

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.