L1 Retrotransposition Transduces Nonrepetitive DNA throughout Cancer Genomes

Long interspersed nuclear element 1 (L1) retrotransposons are abundant repetitive DNA elements that hijack the cellular transcription and translation machinery to copy and reinsert themselves across the human genome. Mobilization of L1 elements in the germline contributes greatly to genetic diversity, and evidence of spontaneous L1 mobilization has been observed in tumors. Neighboring nonrepetitive DNA sequences can also be mobilized during L1 retrotransposition in a process known as 3′ transduction, but whether this class of retrotransposition event is prevalent in human cancer genomes is unclear. Tubio, Li, Ju, and colleagues developed a bioinformatic pipeline to detect somatic L1 retrotransposition events in 12 different cancer types using whole-genome sequencing data from matched tumor and normal samples of 244 patients. At least one somatic L1 retrotransposition event was found in 53% of patients, most frequently those with colon cancer or lung cancer. Overall, 3′ transductions were identified in 25% of patients, and accounted for 24% of all somatic L1 retrotransposition events detected. The activity of individual L1 elements was heterogeneous, with the vast majority of 3′ transductions originating from relatively few L1 loci. L1 element activity also varied between cancer types and fluctuated during evolution of individual tumors, and was correlated with L1 promoter hypomethylation. Somatic retrotranspositions preferentially inserted into intergenic or heterochromatic regions, but coding regions were sometimes captured by somatic 3′ transductions, with proximal exons or entire genes mobilized to different genomic loci as a result of 2.3% of L1 retrotransposition events, as were putative regulatory regions, with DNase I hypersensitive sites and transcription factor binding motifs copied and inserted elsewhere in the genome by 6.6% and 13.1% of L1 retrotransposition events, respectively. Although larger, integrative studies are needed to assess the functional consequences of 3′ transduction during tumorigenesis, these findings indicate that this type of somatic retrotransposition contributes significantly to structural variation in cancer genomes.

Tubio JM, Li Y, Ju YS, Martincorena I, Cooke SL, Tojo M, et al. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 2014;345:1251343.

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