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

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 NawrothUlrika 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

Department of Urology

21 Citations (Scopus)

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.

Original language	English
Article number	2301
Journal	Nature Genetics
Volume	57
Issue number	1
Pages (from-to)	115-125
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-024-02030-z
Publication status	Published - 3 Jan 2025

Keywords

Humans
Urinary Bladder Neoplasms/genetics
Female
Genomics/methods
Male
Mutation
Receptor, Fibroblast Growth Factor, Type 3/genetics
Exome Sequencing
Aged
Tumor Suppressor Protein p53/genetics
Loss of Heterozygosity
Middle Aged
Whole Genome Sequencing
Neoplasm Staging
Genomic Instability

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10.1038/s41588-024-02030-z

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Prip, F., Lamy, P., Lindskrog, S. V., Strandgaard, T., Nordentoft, I., Birkenkamp-Demtröder, K., Birkbak, N. J., Kristjánsdóttir, N., Kjær, A., Andreasen, T. G., Ahrenfeldt, J., Pedersen, J. S., Rasmussen, A. M., Hermann, G. G., Mogensen, K., Petersen, A. C., Hartmann, A., Grimm, M.-O., Horstmann, M., ... Dyrskjøt, L. (2025). Comprehensive genomic characterization of early-stage bladder cancer. Nature Genetics, 57(1), 115-125. Article 2301. https://doi.org/10.1038/s41588-024-02030-z

Prip, F, Lamy, P, Lindskrog, SV, Strandgaard, T, Nordentoft, I, Birkenkamp-Demtröder, K, Birkbak, NJ, Kristjánsdóttir, N, Kjær, A, Andreasen, TG, Ahrenfeldt, J, Pedersen, JS, Rasmussen, AM, Hermann, GG, Mogensen, K, Petersen, AC, Hartmann, A, Grimm, M-O, Horstmann, M, Nawroth, R, Segersten, U, Sikic, D, van Kessel, KEM, Zwarthoff, EC, Maurer, T, Simic, T, Malmström, P-U, Malats, N, Jensen, JB, UROMOL Consortium, Real, FX & Dyrskjøt, L 2025, 'Comprehensive genomic characterization of early-stage bladder cancer', Nature Genetics, vol. 57, no. 1, 2301, pp. 115-125. https://doi.org/10.1038/s41588-024-02030-z

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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.",

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T1 - Comprehensive genomic characterization of early-stage bladder cancer

AU - Prip, Frederik

AU - Lamy, Philippe

AU - Lindskrog, Sia Viborg

AU - Strandgaard, Trine

AU - Nordentoft, Iver

AU - Birkenkamp-Demtröder, Karin

AU - Birkbak, Nicolai Juul

AU - Kristjánsdóttir, Nanna

AU - Kjær, Asbjørn

AU - Andreasen, Tine G

AU - Ahrenfeldt, Johanne

AU - Pedersen, Jakob Skou

AU - Rasmussen, Asta Mannstaedt

AU - Hermann, Gregers G

AU - Mogensen, Karin

AU - Petersen, Astrid C

AU - Hartmann, Arndt

AU - Grimm, Marc-Oliver

AU - Horstmann, Marcus

AU - Nawroth, Roman

AU - Segersten, Ulrika

AU - Sikic, Danijel

AU - van Kessel, Kim E M

AU - Zwarthoff, Ellen C

AU - Maurer, Tobias

AU - Simic, Tatjana

AU - Malmström, Per-Uno

AU - Malats, Núria

AU - Jensen, Jørgen Bjerggaard

AU - UROMOL Consortium

AU - Real, Francisco X

AU - Dyrskjøt, Lars

PY - 2025/1/3

Y1 - 2025/1/3

N2 - 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.

AB - 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.

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KW - Urinary Bladder Neoplasms/genetics

KW - Female

KW - Genomics/methods

KW - Male

KW - Mutation

KW - Receptor, Fibroblast Growth Factor, Type 3/genetics

KW - Exome Sequencing

KW - Aged

KW - Tumor Suppressor Protein p53/genetics

KW - Loss of Heterozygosity

KW - Middle Aged

KW - Whole Genome Sequencing

KW - Neoplasm Staging

KW - Genomic Instability

UR - https://www.scopus.com/pages/publications/85214112361

U2 - 10.1038/s41588-024-02030-z

DO - 10.1038/s41588-024-02030-z

M3 - Journal article

C2 - 39753772

SN - 1061-4036

VL - 57

SP - 115

EP - 125

JO - Nature Genetics

JF - Nature Genetics

IS - 1

M1 - 2301

ER -

Comprehensive genomic characterization of early-stage bladder cancer

Abstract

Keywords

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