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

Jose M C Tubio, Yilong Li, Young Seok Ju, Inigo Martincorena, Susanna L Cooke, Marta Tojo, Gunes Gundem, Christodoulos P Pipinikas, Jorge Zamora, Keiran Raine, Andrew Menzies, Pablo Roman-Garcia, Anthony Fullam, Moritz Gerstung, Adam Shlien, Patrick S Tarpey, Elli Papaemmanuil, Stian Knappskog, Peter Van Loo, Manasa RamakrishnaHelen R Davies, John Marshall, David C Wedge, Jon W Teague, Adam P Butler, Serena Nik-Zainal, Ludmil Alexandrov, Sam Behjati, Lucy R Yates, Niccolo Bolli, Laura Mudie, Claire Hardy, Sancha Martin, Stuart McLaren, Sarah O'Meara, Elizabeth Anderson, Mark Maddison, Stephen Gamble, Christopher Foster, Anne Y Warren, Hayley Whitaker, Daniel Brewer, Rosalind Eeles, Colin Cooper, David Neal, Andy G Lynch, Tapio Visakorpi, William B Isaacs, Laura van't Veer, Carlos Caldas, ICGC Breast Cancer Group

Research output: Contribution to journalArticlepeer-review

210 Citations (Scopus)

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.
Original languageEnglish
Article number1251343
JournalScience
Volume345
Issue number6196
DOIs
Publication statusPublished - 1 Aug 2014

Keywords

  • Carcinogenesis
  • Chromatin
  • DNA Transposable Elements
  • Exons
  • Genome, Human
  • Humans
  • Long Interspersed Nucleotide Elements
  • Mutagenesis, Insertional
  • Neoplasms
  • Transduction, Genetic
  • Translocation, Genetic

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