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

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

Cancer cell (2015-02-12)

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-Jones, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Tomas Acha, Maureen J O'Sullivan, Peter K Bode, Felix Niggli, Godelieve A Tytgat, Harm van Tinteren, Marry M van den Heuvel-Eibrink, Eckart Meese, Christian Vokuhl, Ivo Leuschner, Norbert Graf, Roland Eils, Stefan M Pfister, Marcel Kool, Manfred Gessler

PMID25670083

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.

MATERIALS

Product Number

Brand

Product Description

HPA001893

Sigma-Aldrich

Anti-SIX1 antibody produced in rabbit, Prestige Antibodies^® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution