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; Francisco X. Real; Lars Dyrskjøt; UROMOL Consortium

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, Francisco X. Real, Lars Dyrskjøt^*, UROMOL Consortium

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

2 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	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 - Jan 2025

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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., ... UROMOL Consortium (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

@article{a1473982e6644e40a8838d322d8645e2,

title = "Comprehensive genomic characterization of early-stage bladder cancer",

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.",

author = "Frederik Prip and Philippe Lamy and Lindskrog, {Sia Viborg} and Trine Strandgaard and Iver Nordentoft and Karin Birkenkamp-Demtr{\"o}der and Birkbak, {Nicolai Juul} and Nanna Kristj{\'a}nsd{\'o}ttir and Asbj{\o}rn Kj{\ae}r and Andreasen, {Tine G.} and Johanne Ahrenfeldt and Pedersen, {Jakob Skou} and Rasmussen, {Asta Mannstaedt} and Hermann, {Gregers G.} and Karin Mogensen and Petersen, {Astrid C.} and Arndt Hartmann and Grimm, {Marc Oliver} and Marcus Horstmann and Roman Nawroth and Ulrika Segersten and Danijel Sikic and {van Kessel}, {Kim E.M.} and Zwarthoff, {Ellen C.} and Tobias Maurer and Tatjana Simic and Malmstr{\"o}m, {Per Uno} and N{\'u}ria Malats and Jensen, {J{\o}rgen Bjerggaard} and Real, {Francisco X.} and Lars Dyrskj{\o}t and {UROMOL Consortium}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jan,

doi = "10.1038/s41588-024-02030-z",

language = "English",

volume = "57",

pages = "115--125",

journal = "Nature Genetics",

issn = "1061-4036",

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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, MO, Horstmann, M, Nawroth, R, Segersten, U, Sikic, D, van Kessel, KEM, Zwarthoff, EC, Maurer, T, Simic, T, Malmström, PU, Malats, N, Jensen, JB, Real, FX, Dyrskjøt, L & UROMOL Consortium 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

TY - JOUR

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 - Real, Francisco X.

AU - Dyrskjøt, Lars

AU - UROMOL Consortium

PY - 2025/1

Y1 - 2025/1

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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U2 - 10.1038/s41588-024-02030-z

DO - 10.1038/s41588-024-02030-z

M3 - Journal article

C2 - 39753772

AN - SCOPUS:85214112361

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

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