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

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

doi:https://doi.org/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

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 VersteegTomas 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

Research output: Contribution to journal › Article › Academic › peer-review

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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 SIX/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

Original language	English
Pages (from-to)	298-311
Journal	Cancer cell
Volume	27
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2015.01.002
Publication status	Published - 2015

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https://doi.org/10.1016/j.ccell.2015.01.002

Cite this

Wegert, J., Ishaque, N., Vardapour, R., Geörg, C., Gu, Z., Bieg, M., Ziegler, B., Bausenwein, S., Nourkami, N., Ludwig, N., Keller, A., Grimm, C., Kneitz, S., Williams, R. D., Chagtai, T., Pritchard-Jones, K., van Sluis, P., Volckmann, R., Koster, J., ... Gessler, M. (2015). Mutations in the SIX1/2 Pathway and the DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal Type Wilms Tumors. Cancer cell, 27(2), 298-311. https://doi.org/10.1016/j.ccell.2015.01.002

@article{6647e197b61145dd9c73a8d9bf5a8fad,

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 SIX/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",

author = "Jenny Wegert and Naveed Ishaque and Romina Vardapour and Christina Ge{\"o}rg and Zuguang Gu and Matthias Bieg and Barbara Ziegler and Sabrina Bausenwein and Nasenien Nourkami and Nicole Ludwig and Andreas Keller and Clemens Grimm and Susanne Kneitz and Williams, {Richard D.} and Tas Chagtai and Kathy Pritchard-Jones and {van Sluis}, Peter and Richard Volckmann and Jan Koster and Rogier Versteeg and Tomas Acha and O'Sullivan, {Maureen J.} and Bode, {Peter K.} and Felix Niggli and Tytgat, {Godelieve A.} and {van Tinteren}, Harm and {van den Heuvel-Eibrink}, {Marry M.} and Eckart Meese and Christian Vokuhl and Ivo Leuschner and Norbert Graf and Roland Eils and Pfister, {Stefan M.} and Marcel Kool and Manfred Gessler",

year = "2015",

doi = "https://doi.org/10.1016/j.ccell.2015.01.002",

language = "English",

volume = "27",

pages = "298--311",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

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Wegert, J, Ishaque, N, Vardapour, R, Geörg, C, Gu, Z, Bieg, M, Ziegler, B, Bausenwein, S, Nourkami, N, Ludwig, N, Keller, A, Grimm, C, Kneitz, S, Williams, RD, Chagtai, T, Pritchard-Jones, K, van Sluis, P, Volckmann, R , Koster, J , Versteeg, R, Acha, T, O'Sullivan, MJ, Bode, PK, Niggli, F, Tytgat, GA, van Tinteren, H, van den Heuvel-Eibrink, MM, Meese, E, Vokuhl, C, Leuschner, I, Graf, N, Eils, R, Pfister, SM, Kool, M & Gessler, M 2015, 'Mutations in the SIX1/2 Pathway and the DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal Type Wilms Tumors', Cancer cell, vol. 27, no. 2, pp. 298-311. https://doi.org/10.1016/j.ccell.2015.01.002

TY - JOUR

T1 - Mutations in the SIX1/2 Pathway and the DROSHA/DGCR8 miRNA Microprocessor Complex Underlie High-Risk Blastemal Type Wilms Tumors

AU - Wegert, Jenny

AU - Ishaque, Naveed

AU - Vardapour, Romina

AU - Geörg, Christina

AU - Gu, Zuguang

AU - Bieg, Matthias

AU - Ziegler, Barbara

AU - Bausenwein, Sabrina

AU - Nourkami, Nasenien

AU - Ludwig, Nicole

AU - Keller, Andreas

AU - Grimm, Clemens

AU - Kneitz, Susanne

AU - Williams, Richard D.

AU - Chagtai, Tas

AU - Pritchard-Jones, Kathy

AU - van Sluis, Peter

AU - Volckmann, Richard

AU - Koster, Jan

AU - Versteeg, Rogier

AU - Acha, Tomas

AU - O'Sullivan, Maureen J.

AU - Bode, Peter K.

AU - Niggli, Felix

AU - Tytgat, Godelieve A.

AU - van Tinteren, Harm

AU - van den Heuvel-Eibrink, Marry M.

AU - Meese, Eckart

AU - Vokuhl, Christian

AU - Leuschner, Ivo

AU - Graf, Norbert

AU - Eils, Roland

AU - Pfister, Stefan M.

AU - Kool, Marcel

AU - Gessler, Manfred

PY - 2015

Y1 - 2015

N2 - 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 SIX/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

AB - 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 SIX/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

U2 - https://doi.org/10.1016/j.ccell.2015.01.002

DO - https://doi.org/10.1016/j.ccell.2015.01.002

M3 - Article

C2 - 25670083

SN - 1535-6108

VL - 27

SP - 298

EP - 311

JO - Cancer cell

JF - Cancer cell

IS - 2

ER -