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

Tubio, Jose M. C., Li, Yilong, Ju, Young S., Martincorena, Inigo, Cooke, Susanna L., Tojo, Marta, Gundem, Gunes, Pipinikas, Christodoulos P., Zamora, Jorge, Raine, Keiran, Menzies, Andrew, Roman-Garcia, Pablo, Fullam, Anthony, Gerstung, Moritz, Shlien, Adam, Tarpey, Patrick S., Papaemmanuil, Elli, Knappskog, Stian, Van Loo, Peter, Ramakrishna, Manasa, Davies, Helen R., Marshall, John, Wedge, David C., Teague, Jon W., Butler, Adam P., Nik-Zainal, Serena, Alexandrov, Ludmil, Behjati, Sam, Yates, Lucy R., Bolli, Niccolo, Mudie, Laura, Hardy, Claire, Martin, Sancha, McLaren, Stuart, O'Meara, Sarah, Anderson, Elizabeth, Maddison, Mark, Gamble, Stephen, Foster, Christopher, Warren, Anne Y., Whitaker, Hayley, Brewerm Daniel, Eeles, Rosalind, Cooper, Colin, Neal, David, Lynch, Andy G., Visakorpi, Tapio, Isaacs, William B., Van't Veer, Laura, Caldas, Carlos, Desmedt, Christine, Sotiriou, Christos, Aparicio, Sam, Foekensm, John A., Eyfjord, Jorunn Erla, Lakhani, Sunil R., Thomas, Gilles, Myklebost, Ola, Span, Paul N., Borresen-Dale, Anne-Lise, Richardson, Andrea L., Van De Vijver, Marc, Vincent-Salomon, Anne, Van den Eynden, Gert G., Flanagan, Adrienne M., Futreal, P. Andrew, Janes, Sam M., Bova, G. Steven, Stratton, Michael R., McDermott, Ultan, Campbell, Peter J., ICGC Breast Cancer Group, ICGC Bone Cancer Group, ICGC Prostate Cancer Group and Simpson, Peter (2014) Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science, 345 6196: 1251343.1-1251343.12. doi:10.1126/science.1251343

Author Tubio, Jose M. C.
Li, Yilong
Ju, Young S.
Martincorena, Inigo
Cooke, Susanna L.
Tojo, Marta
Gundem, Gunes
Pipinikas, Christodoulos P.
Zamora, Jorge
Raine, Keiran
Menzies, Andrew
Roman-Garcia, Pablo
Fullam, Anthony
Gerstung, Moritz
Shlien, Adam
Tarpey, Patrick S.
Papaemmanuil, Elli
Knappskog, Stian
Van Loo, Peter
Ramakrishna, Manasa
Davies, Helen R.
Marshall, John
Wedge, David C.
Teague, Jon W.
Butler, Adam P.
Nik-Zainal, Serena
Alexandrov, Ludmil
Behjati, Sam
Yates, Lucy R.
Bolli, Niccolo
Mudie, Laura
Hardy, Claire
Martin, Sancha
McLaren, Stuart
O'Meara, Sarah
Anderson, Elizabeth
Maddison, Mark
Gamble, Stephen
Foster, Christopher
Warren, Anne Y.
Whitaker, Hayley
Brewerm Daniel
Eeles, Rosalind
Cooper, Colin
Neal, David
Lynch, Andy G.
Visakorpi, Tapio
Isaacs, William B.
Van't Veer, Laura
Caldas, Carlos
Desmedt, Christine
Sotiriou, Christos
Aparicio, Sam
Foekensm, John A.
Eyfjord, Jorunn Erla
Lakhani, Sunil R.
Thomas, Gilles
Myklebost, Ola
Span, Paul N.
Borresen-Dale, Anne-Lise
Richardson, Andrea L.
Van De Vijver, Marc
Vincent-Salomon, Anne
Van den Eynden, Gert G.
Flanagan, Adrienne M.
Futreal, P. Andrew
Janes, Sam M.
Bova, G. Steven
Stratton, Michael R.
McDermott, Ultan
Campbell, Peter J.
ICGC Breast Cancer Group
ICGC Bone Cancer Group
ICGC Prostate Cancer Group
Simpson, Peter
Total Author Count Override 74
Title Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes
Journal name Science   Check publisher's open access policy
ISSN 1095-9203
Publication date 2014-08-01
Year available 2014
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1126/science.1251343
Volume 345
Issue 6196
Start page 1251343.1
End page 1251343.12
Total pages 12
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Collection year 2015
Language eng
Formatted abstract

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.


The activity of individual L1 elements fluctuates during tumor evolution. In a lung tumor, hundreds of 3′ transductions arose from a small number of active L1 source elements (colored circles on outer rim of circle). As the tumor evolved from the preinvasive common ancestor to invasive cancer, individual elements exhibited variable activity over time.


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.


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.


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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: UQ Centre for Clinical Research Publications
Official 2015 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 54 times in Thomson Reuters Web of Science Article | Citations
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