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

Tubio, J. M.; Li, Y.; Ju, Y. S.; Martincorena, I.; Cooke, S. L.; Tojo Castro, Marta; 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.; 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.; Group, ICGC Breast Cancer; Group, ICGC Bone Cancer; Group, ICGC Prostate Cancer

doi:10.1126/science.1251343

Tubio, J. M.; Li, Y.; Ju, Y. S.; Martincorena, I.; Cooke, S. L.; Tojo Castro, Marta; 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.; 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.; Group, ICGC Breast Cancer; Group, ICGC Bone Cancer; Group, ICGC Prostate Cancer

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URI: http://hdl.handle.net/20.500.11940/6788

PMID: 25082706

DOI: 10.1126/science.1251343

ISSN: 0036-8075

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Texto completo disponible por cortesía de Science . 2014 Aug 1;345(6196):1251343. doi: 10.1126/science.1251343. (1.397Mb)

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2014

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SCIENCE

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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.

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