A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Dynamic and Ongoing De Novo L1 Retrotransposition Contributes to Genome Plasticity and Intrapatient Heterogeneity in Ovarian Cancer
Tekijät: 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
Kustantaja: American Association for Cancer Research
Julkaisuvuosi: 2026
Lehti: Cancer Research
Vuosikerta: 86
Numero: 4
Aloitussivu: 1073
Lopetussivu: 1088
ISSN: 0008-5472
eISSN: 1538-7445
DOI: https://doi.org/10.1158/0008-5472.CAN-24-4419
Julkaisun avoimuus kirjaamishetkellä: Avoimesti saatavilla
Julkaisukanavan avoimuus : Osittain avoin julkaisukanava
Verkko-osoite: https://doi.org/10.1158/0008-5472.can-24-4419
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/505368945
Rinnakkaistallenteen lisenssi: CC BY NC ND
Rinnakkaistallennetun julkaisun versio: Kustantajan versio
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
Julkaisussa olevat rahoitustiedot:
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).
