Nature communications · 2026
Multiomic profiling links L1 retrotransposition to genomic instability and ecDNA in bladder cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Pribus Sophia J, Osredek Ivana, Otoničar Jan, Simovic-Lorenz Milena, Giovenino Chiara, Rademacher Anne, Wille Sina Jasmin, Berzain Battioni Cecilia, Scherer Michael, Manzano-Sanchez Sergio, Kienzle Andreas, Parekh Urja, Villacorta Laura, Benes Vladimir, Sant Pooja, Mallm Jan-Philipp, Brand Karsten, Rippe Karsten, Riemer Angelika B, Sültmann Holger, Plass Christoph, Stankovic Mladen, Korbel Jan O, Rausch Tobias, Ernst Aurélie
Аннотация
Bladder cancer is frequent and highly recurrent. Despite recent advances, knowledge gaps remain in molecular mechanisms underlying disease progression. In this study, we apply integrated multi-omic analyses to a cohort of 48 bladder cancer patients to comprehensively profile genetic, epigenetic, transcriptomic, and spatial features. Combining cell-free DNA sequencing, long-read tumor DNA-sequencing, RNA-sequencing, and spatial transcriptomics, we explore molecular alterations driving bladder cancer. We find frequent somatic LINE-1 (L1) insertions, and show that these L1 insertions are active and occur early in bladder cancer development. We link somatic L1 insertion with downstream genomic rearrangements and chromosomal instability, including increased structural variant and extrachromosomal DNA (ecDNA) counts in patients with high L1 counts. We identify variable ecDNA enrichment across tissue architecture, with highest enrichment overlapping differential expression of APOBEC3B and immune response pathways. In summary, our results support a model whereby L1 retrotransposition triggers downstream genomic instability and viral mimicry response.