Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes
Open accessAbstract
Introduction: The human genome is peppered with mobile repetitive elements called long interspersed nuclear element–1 (L1) retrotransposons. Propagating through RNA and cDNA intermediates, these molecular parasites copy and insert themselves throughout the genome, with potentially disruptive effects on neighboring genes or regulatory sequences. In the germ line, unique sequence downstream of L1 elements can also be retrotransposed if transcription continues beyond the repeat, a process known as 3′ transduction. There has been growing interest in retrotransposition and 3′ transduction as a possible source of somatic mutations during tumorigenesis. Rationale: To explore whether 3′ transductions are frequent in cancer, we developed a bioinformatic algorithm for identifying somatically acquired retrotranspositions in cancer genomes. We applied our algorithm to 290 cancer samples from 244 patients across 12 tumor types. The unique downstream sequence mobilized with 3′ transductions effectively fingerprints the L1 source element, providing insights into the activity of individual L1 loci across the genome. Results: Across the 290 samples, we identified 2756 somatic L1 retrotranspositions. Tumors from 53% of patients had at least one such event, with colorectal and lung cancers being most frequently affected (93% and 75% of patients, respectively). Somatic 3′ transductions comprised 24% of events, half of which represented mobilizations of unique sequence alone, without any accompanying L1 sequence. Overall, 95% of 3′ transductions identified derived from only 72 germline L1 source elements, with as few as four loci accounting for 50% of events. In a given sample, the same source element could generate 50 or more somatic transductions, scattered extensively across the genome. About 5% of somatic transductions arose from L1 source elements that were themselves somatic retrotranspositions. In three of the cases in which we sequenced more than one sample from a patient’s tumor, we were able to place 3′ transductions on the phylogenetic tree. We found that the activity of individual source elements fluctuated during tumor evolution, with different subclones exhibiting much variability in which elements were “on” and which were “off.” The ability to identify the individual L1 source elements active in a given tumor enabled us to study the promoter methylation of those elements specifically. We found that 3′ transduction activity in a patient’s tumor was always associated with hypomethylation of that element. Overall, 2.3% of transductions distributed exons or entire genes to other sites in the genome, and many more mobilized deoxyribonuclease I (DNAse-I) hypersensitive sites or transcription factor binding sites identified by the ENCODE project. Occasionally, somatic L1 insertions inserted near coding sequence and redistributed these exons elsewhere in the genome. However, we found no general effects of retrotranspositions on transcription levels of genes at the insertion points and no evidence for aberrant RNA species resulting from somatically acquired transposable elements. Indeed, as with germline retrotranspositions, somatic insertions exhibited a strong enrichment in heterochromatic, gene-poor regions of the genome. Conclusion: Somatic 3′ transduction occurs frequently in human tumors, and in some cases transduction events can scatter exons, genes, and regulatory elements widely across the genome. Dissemination of these sequences appears to be due to a small number of highly active L1 elements, whose activity can wax and wane during tumor evolution. The majority of the retrotransposition events are likely to be harmless “passenger” mutations.
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Multiple de novo somatic insertions and associated rearrangements have been identified in human cancers, in some cases numbering in the hundreds for an individual tumor.
“Subsequent efforts identified multiple de novo somatic insertions and associated rearrangements in human cancers, in some cases numbering in the hundreds for an individual tumor86–89.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [88]
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- Authors
- Tubio, J. M. C., Li, Y., Ju, Y. S., Martincorena, I., Cooke, S. L., Tojo, M., Gundem, G., Pipinikas, C. P., Zamora, J., Raine, K., Menzies, A., Roman-Garcia, P., Fullam, A., Gerstung, M., Shlien, A., Tarpey, P. S., Papaemmanuil, E., Knappskog, S., Van Loo, P., Ramakrishna, M., Davies, H. R., Marshall, J., Wedge, D. C., Teague, J. W., Butler, A. P., Nik-Zainal, S., Alexandrov, L., Behjati, S., Yates, L. R., Bolli, N., Mudie, L., Hardy, C., Martin, S., McLaren, S., O’Meara, S., Anderson, E., Maddison, M., Gamble, S., ICGC Breast Cancer Group, ICGC Bone Cancer Group, ICGC Prostate Cancer Group, Foster, C., Warren, A. Y., Whitaker, H., Brewer, D., Eeles, R., Cooper, C., Neal, D., Lynch, A. G., Visakorpi, T., Isaacs, W. B., van't Veer, L., Caldas, C., Desmedt, C., Sotiriou, C., Aparicio, S., Foekens, J. A., Eyfjörd, J. E., Lakhani, S. R., Thomas, G., Myklebost, O., Span, P. N., Børresen-Dale, A.-L., Richardson, A. L., Van de Vijver, M., Vincent-Salomon, A., Van den Eynden, G. G., Flanagan, A. M., Futreal, P. A., Janes, S. M., Bova, G. S., Stratton, M. R., McDermott, U., & Campbell, P. J.
- Affiliations
- Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
- Wellcome Sanger Institute (GB)
- Universidade de Santiago de Compostela (ES)
- University College London (GB)
- Haukeland University Hospital (NO)
- University of Liverpool (GB)
- National Health Service (GB)
- University of Cambridge (GB)
- University of East Anglia (GB)
- Institute of Cancer Research (GB)
- Johns Hopkins University (US)
- Université Libre de Bruxelles (BE)
- Netherlands Cancer Institute, Amsterdam, Netherlands.
- BC Cancer Agency (CA)
- British Columbia Cancer Agency, Vancouver, Canada.
- Lyon 1 Université (FR)
- Cancer Research Laboratory, University of Iceland, Reykjavik, Iceland.
- The University of Queensland (AU)
- Oslo University Hospital (NO)
- Amsterdam UMC Location University of Amsterdam (NL)
- Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
- GZA Ziekenhuizen Campus Sint-Augustinus (BE)
- Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
- Institut Bergonié, 229 cours de l’Argone, 33076 Bordeaux, France.
- Translational Cancer Research Unit and Department of Pathology, GZA Hospitals, Antwerp, Belgium.
- Royal National Orthopaedic Hospital (GB)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Li, Yilong
- Ju, Young Seok
- ORCID
- Li, Yilong
- Ju, Young Seok
- Gundem, Gunes
- Pipinikas, Christodoulos P.
- Zamora, Jorge
- Raine, Keiran
- Menzies, Andrew
- Fullam, Anthony
- Gerstung, Moritz
- Shlien, Adam
- Tarpey, Patrick S.
- Papaemmanuil, Elli
- Knappskog, Stian
- Ramakrishna, Manasa
- Davies, Helen R.
- Marshall, John
- Wedge, David C.
- Teague, Jon W.
- Alexandrov, Ludmil
- Behjati, Sam
- Yates, Lucy R.
- McLaren, Stuart
- Foster, Christopher
- Warren, Anne Y.
- Whitaker, Hayley
- Brewer, Daniel
- Eeles, Rosalind
- Neal, David
- Lynch, Andy G.
- Visakorpi, Tapio
- Isaacs, William B.
- Caldas, Carlos
- Desmedt, Christine
- Sotiriou, Christos
- Lakhani, Sunil R.
- Thomas, Gilles
- Myklebost, Ola
- Span, Paul N.
- Richardson, Andrea L.
- Flanagan, Adrienne M.
- Futreal, P. Andrew
- Janes, Sam M.
- Bova, G. Steven
- Stratton, Michael R.
- McDermott, Ultan
- Venue
- Science
- Published
- 2014-08
- Volume
- 345
- Issue
- 6196
- Pages
- 1251343-1251343
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4380235
- OpenAlex
- W2154422767
- Cited by
- 412
- References
- 47
- Citations by year
- 2026: 22 · 2025: 34 · 2024: 26 · 2023: 28 · 2022: 34 · 2021: 43 · 2020: 36 · 2019: 35 · 2018: 29 · 2017: 38 · 2016: 48 · 2015: 37 · 2014: 2
- FWCI
- 48.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Funders
- Wellcome Trust (091730, 088340, WT100183MA)
- Cancer Research UK (15007, 19556, 14835, 17528, 16942, C5047/A14835)
- National Institute for Health and Care Research (NF-SI-0611-10154)
- Academy of Medical Sciences (AMS-SGCL6-Bolli)
- Rosetrees Trust (M23-F1, M35-F1-CD1)
- Biotechnology and Biological Sciences Research Council (BBS/E/F/00044431, BBS/E/F/00042686)
- National Cancer Institute (P30CA006973)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- LINE-1 retrotransposons, somatic retrotransposition, cancer genome, carcinogenesis, promoter methylation, tumor evolution, subclonal heterogeneity, colorectal cancer, lung cancer, somatic mutations
- MeSH terms
- Chromatin, DNA Transposable Elements, Exons, Humans, Neoplasms, Transduction, Genetic, Translocation, Genetic, Genome, Human, Mutagenesis, Insertional, Long Interspersed Nucleotide Elements, Carcinogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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