Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma.
Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Jakob
J
Hedegaard
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Philippe
P
Lamy
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Iver
I
Nordentoft
Section of Pathology, Fundació Puigvert, University Autonoma de Barcelona, Barcelona 08025, Spain.
Ferran
F
Algaba
Department of Pathology, Aarhus University Hospital, Aarhus 8000, Denmark.
Søren
S
Høyer
Department of Pathology, Aarhus University Hospital, Aarhus 8000, Denmark.
Benedicte Parm
BP
Ulhøi
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Søren
S
Vang
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Thomas
T
Reinert
Department of Urology, Frederiksberg Hospital, Frederiksberg 2000, Denmark.
Gregers G
GG
Hermann
Department of Urology, Frederiksberg Hospital, Frederiksberg 2000, Denmark.
Karin
K
Mogensen
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Mathilde Borg Houlberg
MBH
Thomsen
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Morten Muhlig
MM
Nielsen
Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Mirari
M
Marquez
Department of Surgical Sciences, Uppsala University, Uppsala 75185, Sweden.
Ulrika
U
Segersten
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund 22100, Sweden.
Mattias
M
Aine
Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund 22100, Sweden.
Mattias
M
Höglund
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Karin
K
Birkenkamp-Demtröder
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Niels
N
Fristrup
Department of Urology, Aarhus University Hospital, Aarhus 8200, Denmark.
Michael
M
Borre
Institute of Pathology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen 91054, Germany.
Arndt
A
Hartmann
Institute of Pathology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen 91054, Germany.
Robert
R
Stöhr
Department of Urology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen 91054, Germany.
Sven
S
Wach
Department of Urology, University Hospital Erlangen, Friedrich Alexander-University Erlangen-Nürnberg, Erlangen 91054, Germany.
Bastian
B
Keck
Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich 81675, Germany.
Anna Katharina
AK
Seitz
Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich 81675, Germany.
Roman
R
Nawroth
Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich 81675, Germany.
Tobias
T
Maurer
Faculty of Medicine, Clinic of Urology, Clinical Centre of Serbia, University of Belgrade, 11000 Belgrade, Serbia.
Cane
C
Tulic
Faculty of Medicine, Institute of Medical and Clinical Biochemistry, University of Belgrade, 11000 Belgrade, Serbia.
Tatjana
T
Simic
Department of Urology, Saarland University, Homburg 66421, Germany.
Kerstin
K
Junker
Department of Urology, Friedrich-Schiller-University Jena, Jena 07737, Germany.
Marcus
M
Horstmann
Department of Urology, Aalborg University Hospital, Aalborg 9000, Denmark.
Niels
N
Harving
Department of Pathology, Aalborg University Hospital, Aalborg 9000, Denmark.
Astrid Christine
AC
Petersen
Systems Biology Department, University of Vic, Vic, Barcelona 08500, Spain.
M Luz
ML
Calle
Department of Public Health, Erasmus Medical Centre, 3015 CE Rotterdam, the Netherlands.
Ewout W
EW
Steyerberg
Department of Pathology, Erasmus Medical Centre, 3015 CE Rotterdam, the Netherlands.
Willemien
W
Beukers
Department of Pathology, Erasmus Medical Centre, 3015 CE Rotterdam, the Netherlands.
Kim E M
KEM
van Kessel
Department of Urology, Aarhus University Hospital, Aarhus 8200, Denmark.
Jørgen Bjerggaard
JB
Jensen
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Jakob Skou
JS
Pedersen
Department of Surgical Sciences, Uppsala University, Uppsala 75185, Sweden.
Per-Uno
PU
Malmström
Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
Núria
N
Malats
Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona 08003, Spain.
Francisco X
FX
Real
Department of Pathology, Erasmus Medical Centre, 3015 CE Rotterdam, the Netherlands.
Ellen C
EC
Zwarthoff
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark.
Torben Falck
TF
Ørntoft
Department of Molecular Medicine, Aarhus University Hospital, Aarhus 8200, Denmark. Electronic address: lars@clin.au.dk.
Lars
L
Dyrskjøt
D000071478:APOBEC Deaminases / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D062085:RNA, Long Noncoding / Q000235:genetics; D017423:Sequence Analysis, RNA / Q000379:methods*; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology*
D014408:Biomarkers, Tumor; D062085:RNA, Long Noncoding; D000071478:APOBEC Deaminases