| Title: |
Dynamic and Ongoing De Novo L1 Retrotransposition Contributes to Genome Plasticity and Intrapatient Heterogeneity in Ovarian Cancer |
| Authors: |
Pradhan, Barun; Oikkonen-Köngäs, Jaana; Zhang, Kaiyang; Botto, Juan Manuel; Eriksson, Minna R.; Sundaresan, Srividhya; Genç, Fatih; Pisanic, Thomas R.; Marín Falco, Matías; 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 |
| Contributors: |
Genome Stability Group; Research Program in Systems Oncology; Faculty of Medicine; Sampsa Hautaniemi / Principal Investigator; HUS Radiology and Pathology; Department of Pathology; HUS Diagnostic Center; Department of Organismal and Evolutionary Biology; Bioinformatics; Department of Biochemistry and Developmental Biology; Medicum |
| Publisher Information: |
American Association for Cancer Research Inc. |
| Publication Year: |
2026 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Chromosomal and Genetic Variations; Cancers |
| Description: |
Long interspersed element-1 (L1) retrotransposons are the only protein-coding active transposable elements in the human genome. Although 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 that they might also play a role in intrapatient tumor heterogeneity. In this study, 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, whereas 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 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 the progenitor tumor. Retrotransposition-associated DNA damage and/or replication stress could be a potential molecular vulnerability for precision cancer medicine approaches.Significance: L1 retrotransposition is a dynamic process that continues at late stages of high-grade serous ovarian cancer and can substantially contribute to intrapatient tumor heterogeneity. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
We would like to thank Dr. Manuela Tumiati, Taina Turunen, and Sabrina Gericke for their technical assistance and sample collection and to Dr. Sanna Vuoristo for experimental advice. HGSC cell lines used in this study were kindly provided by Drs. A. Vaharautio and Krister Wennerberg laboratories. This work was supported in part by the European Union's Horizon 2020 Research and Innovation Programme under grant agreement 965193 (DECIDER), the Sigrid Juselius Foundation, the Cancer Foundation Finland, and the Research Council of Finland (grant number 322178 to L. Kauppi). B. Pradhan was supported by research grants from the Finnish Cultural Foundation. G.J. Faulkner was supported by an Australian National Health and Medical Research Investigator Grant (GNT1173711). We would also like to acknowledge CSC-IT Center for Science, Finland, for computational resources and Biomedicum Functional Genomics Unit (FuGu) for genomics services. The results published here are in part based upon data generated by The Cancer Genome Atlas managed by the NCI and National Human Genome Research Institute. Information about The Cancer Genome Atlas can be found at http://cancergenome.nih.gov. The whole-slide scan images were generated using 3DHISTECH Pannoramic 250 FLASH III digital slide scanner at Finnish Genome Editing Center and analyzed at the Biomedicum Imaging Unit, supported by HiLIFE and the Faculty of Medicine, University of Helsinki, and Biocenter Finland. Generative artificial intelligence assisted in improving clarity and brevity of the author-generated text in parts of the manuscript.; https://hdl.handle.net/10138/629193; 001692415300013 |
| Availability: |
https://hdl.handle.net/10138/629193 |
| Rights: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.F270D29E |
| Database: |
BASE |