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<p>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 (<i>n</i> = 438), shallow whole-genome sequencing (<i>n</i> = 362) and total RNA sequencing (<i>n</i> = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in <i>FGFR3</i> and 17p (affecting <i>TP53</i>) was found in tumors with mutations in <i>FGFR3</i> and <i>TP53</i>, 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.</p>

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Comprehensive genomic characterization of early-stage bladder cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月3日

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  • 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,
  • Kim E. M. van Kessel,
  • Francisco X. Real,
  • Lars Dyrskjøt

摘要

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.