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Science. 2014 Aug 1;345(6196):1251343. doi: 10.1126/science.1251343.

Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes.

Author information

1
Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
2
Department of Physiology, School of Medicine-Center for Resesarch in Molecular Medicine and Chronic Diseases, Instituto de Investigaciones Sanitarias, University of Santiago de Compostela, Spain.
3
Lungs for Living Research Centre, Rayne Institute, University College London (UCL), London, UK.
4
Department of Clinical Science, University of Bergen, Bergen, Norway.
5
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
6
Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium.
7
Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
8
Department of Haematology, University of Cambridge, Cambridge, UK.
9
University of Liverpool and HCA Pathology Laboratories, London, UK.
10
Cancer Research UK (CRUK) Cambridge Institute, University of Cambridge, Cambridge, UK.
11
Institute of Cancer Research, Sutton, London, UK.
12
University of East Anglia, Norwich, UK.
13
Institute of Biosciences and Medical Technology-BioMediTech, University of Tampere and Tampere University Hospital, Tampere, Finland.
14
Johns Hopkins University, Baltimore, MD, USA.
15
Netherlands Cancer Institute, Amsterdam, Netherlands.
16
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
17
British Columbia Cancer Agency, Vancouver, Canada.
18
Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands.
19
Cancer Research Laboratory, University of Iceland, Reykjavik, Iceland.
20
School of Medicine, University of Queensland, Brisbane, Australia.
21
Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.
22
UQ Centre for Clinical Research, University of Queensland, Brisbane, Australia.
23
Université Lyon 1, Institut National du Cancer (INCa)-Synergie, Lyon, France.
24
Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
25
Department of Radiation Oncology and Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
26
Dana-Farber Cancer Institute, Boston, MA, USA.
27
Department of Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
28
Institut Bergonié, 229 cours de l'Argone, 33076 Bordeaux, France.
29
Institut Curie, Department of Tumor Biology, 26 rue d'Ulm, 75248 Paris cédex 05, France.
30
Translational Cancer Research Unit and Department of Pathology, GZA Hospitals, Antwerp, Belgium.
31
Royal National Orthopaedic Hospital, Middlesex, UK.
32
UCL Cancer Institute, University College London, London, UK.
33
MD Anderson Cancer Center, Houston, TX, USA.
#
Contributed equally

Abstract

Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.

PMID:
25082706
PMCID:
PMC4380235
DOI:
10.1126/science.1251343
[Indexed for MEDLINE]
Free PMC Article

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