Comprehensive genomic characterization of early-stage bladder cancer

Frederik Prip; Philippe Lamy; Sia Viborg Lindskrog; Trine Strandgaard; Iver Nordentoft; Karin Birkenkamp-Demtröder; Nicolai Juul Birkbak; Nanna Kristjánsdóttir; Asbjørn Kjær; Tine G Andreasen; Johanne Ahrenfeldt; Jakob Skou Pedersen; Asta Mannstaedt Rasmussen; Gregers G Hermann; Karin Mogensen; Astrid C Petersen; Arndt Hartmann; Marc-Oliver Grimm; Marcus Horstmann; Roman Nawroth; Ulrika Segersten; Danijel Sikic; Kim E M van Kessel; Ellen C Zwarthoff; Tobias Maurer; Tatjana Simic; Per-Uno Malmström; Núria Malats; Jørgen Bjerggaard Jensen; UROMOL Consortium; Francisco X Real; Lars Dyrskjøt

doi:10.1038/s41588-024-02030-z

Comprehensive genomic characterization of early-stage bladder cancer

Nat Genet. 2025 Jan 3. doi: 10.1038/s41588-024-02030-z. Online ahead of print.

Authors

Frederik Prip^{1

2}, Philippe Lamy¹, Sia Viborg Lindskrog^{1

2}, Trine Strandgaard^{1

2}, Iver Nordentoft¹, Karin Birkenkamp-Demtröder^{1

2}, Nicolai Juul Birkbak^{1

2}, Nanna Kristjánsdóttir^{1

2}, Asbjørn Kjær^{1

2}, Tine G Andreasen^{1

2}, Johanne Ahrenfeldt^{1

2}, Jakob Skou Pedersen^{1

2}, Asta Mannstaedt Rasmussen^{1

2}, Gregers G Hermann³, Karin Mogensen³, Astrid C Petersen⁴, Arndt Hartmann⁵, Marc-Oliver Grimm⁶, Marcus Horstmann⁷, Roman Nawroth⁸, Ulrika Segersten⁹, Danijel Sikic¹⁰, Kim E M van Kessel^{11

12}, Ellen C Zwarthoff¹³, Tobias Maurer¹⁴, Tatjana Simic¹⁵, Per-Uno Malmström⁹, Núria Malats¹⁶, Jørgen Bjerggaard Jensen^{2

17}; UROMOL Consortium; Francisco X Real^{18

19}, Lars Dyrskjøt^{20

21}

Collaborator

UROMOL Consortium:
Kim E M van Kessel

Affiliations

¹ Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
² Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
³ Department of Urology, Herlev Hospital, Copenhagen University, Copenhagen, Denmark.
⁴ Department of Pathology, Aalborg University Hospital, Aalborg, Denmark.
⁵ Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center EMN, Erlangen, Germany.
⁶ Department of Urology, Jena University Hospital, Jena, Germany.
⁷ Department of Urology, University Hospital Essen, Essen, Germany.
⁸ Department of Urology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany.
⁹ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
¹⁰ Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
¹¹ Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹² Department of Urology, Amphia Ziekenhuis, Breda, the Netherlands.
¹³ Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
¹⁴ Department of Urology and Martini-Klinik, University of Hamburg-Eppendorf, Hamburg, Germany.
¹⁵ Institute of Medical and Clinical Biochemistry, Center for Redox Medicine, Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
¹⁶ Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO) and CIBERONC, Madrid, Spain.
¹⁷ Department of Urology, Aarhus University Hospital, Aarhus, Denmark.
¹⁸ Epithelial Carcinogenesis Group, Spanish National Cancer Research Center (CNIO) and CIBERONC, Madrid, Spain.
¹⁹ Medicine and Life Sciences Department, Universitat Pompeu Fabra, Barcelona, Spain.
²⁰ Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. [email protected].
²¹ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark. [email protected].

PMID: 39753772
DOI: 10.1038/s41588-024-02030-z

Abstract

Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification.

Abstract

Grants and funding