Concurrent L1 retrotransposition events promote reciprocal translocations in human tumorigenesis
LINE-1 (L1) retrotransposition generates somatic genomic variation in human cancer, but short-read sequencing has limited our understanding of its structural consequences and dynamics. Using long-read sequencing, we analyzed 10 tumors with exceptionally high retrotransposition activity, comprising over 6,000 somatic events. We reveal that L1-mediated reciprocal translocations occur frequently, typically driven by two concurrent L1 retrotransposition events on non-homologous chromosomes. Using an independent tumor cohort spanning low to high L1 activity, we estimate that retrotransposon-mediated rearrangements arise at a frequency of one event per 60 somatic retrotranspositions. Molecular timing analyses indicate that these events arise early in tumorigenesis, establishing L1 activity as an early driver of chromosomal instability. Our findings demonstrate that L1 contributes substantially to cancer genome evolution in certain tumors.
Authors
- Ana Oitabén (ORCID: https://orcid.org/0000-0002-4877-6145)
- Iago Otero (ORCID: https://orcid.org/0000-0002-7924-693X)
- Eva G. Álvarez (ORCID: https://orcid.org/0000-0002-3522-5088)
- Juan Carlos Zamora (ORCID: https://orcid.org/0000-0002-9243-2999)
- Jorge Rodríguez‐Castro (ORCID: https://orcid.org/0000-0003-2912-9601)
- Mónica Martínez‐Fernández (ORCID: https://orcid.org/0000-0003-1251-0748)
- Daniel García‐Souto (ORCID: https://orcid.org/0000-0002-0997-8799)
- Toby M. Baker (ORCID: https://orcid.org/0000-0002-5183-9047)
- Manuel Blanco (ORCID: https://orcid.org/0000-0001-6328-0335)
- Paula Otero (ORCID: https://orcid.org/0000-0001-7433-7042)
- Iria Díaz-Arias
- Nuria P. Espasandín
- Peter Van Loo
- Sonia Zumalave
- Javier Temes
- Gael Cristofari
- Ana Pequeño-Valtierra
- Martin Santamarina
- Bernardo Rodriguez-Martin
- Jose M. C. Tubio
Institutions
- Centre National de la Recherche Scientifique (FR)
- The University of Texas MD Anderson Cancer Center (US)
- Inserm (FR)
- Universitat Pompeu Fabra (ES)
- Universidade de Santiago de Compostela (ES)
- The Francis Crick Institute (GB)
- Galicia Sur Biomedical Foundation (ES)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR)
- Centre for Genomic Regulation (ES)
- European Molecular Biology Laboratory (DE)
- Instituto de Investigación Sanitaria de Santiago (ES)
Publication Details
- Journal
- Science
- Published
- 2026-02-26
- DOI
- https://doi.org/10.1126/science.aee4513
- Citations
- 1
- Primary Topic
- Chromosomal and Genetic Variations
- Type
- article
- Field-Weighted Citation Impact
- 31.34