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 vanSluis; Richard Volckmann; Jan Koster; Rogier Versteeg; Tomas Acha; Maureen J. O'Sullivan; Peter K. Bode; Felix Niggli; Godelieve A. Tytgat; Harm vanTinteren; Marry M. vandenHeuvel-Eibrink; Eckart Meese; Christian Vokuhl; Ivo Leuschner; Norbert Graf; Roland Eils; Stefan M. Pfister; Marcel Kool; Manfred Gessler

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

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 vanSluis, Richard Volckmann, Jan Koster, Rogier VersteegTomas Acha, Maureen J. O'Sullivan, Peter K. Bode, Felix Niggli, Godelieve A. Tytgat, Harm vanTinteren, Marry M. vandenHeuvel-Eibrink, Eckart Meese, Christian Vokuhl, Ivo Leuschner, Norbert Graf, Roland Eils, Stefan M. Pfister, Marcel Kool, Manfred Gessler

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

225 Citaten (Scopus)

Samenvatting

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.

Originele taal-2	Engels
Pagina's (van-tot)	298-311
Aantal pagina's	14
Tijdschrift	Cancer Cell
Volume	27
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.1016/j.ccell.2015.01.002
Status	Gepubliceerd - 9 feb. 2015
Extern gepubliceerd	Ja

Toegang tot document

10.1016/j.ccell.2015.01.002

Citeer dit

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., vanSluis, 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{5854221a5df34887842ce008ab29538f,

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.",

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 Peter vanSluis 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 Harm vanTinteren and vandenHeuvel-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",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = feb,

day = "9",

doi = "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",

}

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, vanSluis, P, Volckmann, R, Koster, J, Versteeg, R, Acha, T, O'Sullivan, MJ, Bode, PK, Niggli, F, Tytgat, GA, vanTinteren, H, vandenHeuvel-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, nr. 2, blz. 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 - vanSluis, 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 - vanTinteren, Harm

AU - vandenHeuvel-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 - 2015/2/9

Y1 - 2015/2/9

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 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=84922769850&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2015.01.002

DO - 10.1016/j.ccell.2015.01.002

M3 - Article

C2 - 25670083

AN - SCOPUS:84922769850

SN - 1535-6108

VL - 27

SP - 298

EP - 311

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

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

Samenvatting

Toegang tot document

Vingerafdruk

Citeer dit