A1 Refereed original research article in a scientific journal
Dynamic and Ongoing De Novo L1 Retrotransposition Contributes to Genome Plasticity and Intrapatient Heterogeneity in Ovarian Cancer
Authors: Pradhan, Barun; Oikkonen, Jaana; Zhang, Kaiyang; Botto, Juan Manuel.; Eriksson, Minna R.; Sundaresan, Srividhya; Genç, Fatih; Pisanic, Thomas R.; Marin Falco, Matias; Li, Yilin; Pikkusaari, Sanna; Lavikka, Kari; Micoli, Giulia; Marchi, Giovanni; Muranen, Taru A.; Huhtinen, Kaisa; Vähärautio, Anna; Badge, Richard; Burns, Kathleen H.; Hietanen, Sakari; Hynninen, Johanna; Faulkner, Geoffrey J.; Hautaniemi, Sampsa; Kauppi, Liisa
Publisher: American Association for Cancer Research
Publication year: 2026
Journal: Cancer Research
Volume: 86
Issue: 4
First page : 1073
Last page: 1088
ISSN: 0008-5472
eISSN: 1538-7445
DOI: https://doi.org/10.1158/0008-5472.CAN-24-4419
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Partially Open Access publication channel
Web address : https://doi.org/10.1158/0008-5472.can-24-4419
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/505368945
Self-archived copy's licence: CC BY NC ND
Self-archived copy's version: Publisher`s PDF
L1 retrotransposons are the only protein-coding active transposable elements in the human genome. While typically silenced in normal cells, they are highly expressed in many human epithelial cancers, including high-grade serous ovarian cancer (HGSC), and can integrate into the genome through retrotransposition. De novo L1 insertions are known to contribute to genomic instability and cancer evolution in epithelial malignancies, including HGSC, suggesting they might also play a role in intra-patient tumor heterogeneity. Here, we quantified de novo L1 insertions in clinical HGSC specimens and uncovered high heterogeneity in total L1 insertion events (L1 burden) between patients. HGSC tumors with high L1 burden were highly proliferative, while tumors with low or no L1 insertions showed enrichment of immune response and cell death pathways. Although the overall L1 burden was similar across different tumor sites within the same patient, the specific L1 insertions (L1 profiles) diverged significantly more than their single nucleotide variants (SNVs) profiles. Taken together, these findings demonstrate that L1 activity and retrotransposition are highly dynamic in vivo and can contribute substantially to tumor genome plasticity, especially at late stages of cancer progression. The patient-specific propensity of acquiring L1 insertions (L1 burden) could be driven by molecular properties of progenitor tumor. Retrotransposition-associated DNA damage and/or replication stress could be a potential molecular vulnerability for precision cancer medicine approaches.
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Funding information in the publication:
This work was supported in part by the European Union's Horizon 2020 Research and Innovation Programme under grant agreement 965193 (DECIDER), the Sigrid Jusélius Foundation, the Cancer Foundation Finland, and the Research Council of Finland (grant number 322178 to L.K.). B.P. was supported by research grants from the Finnish Cultural Foundation. G.J.F. was supported by an Australian National Health and Medical Research (NHMRC) Investigator Grant (GNT1173711).
