Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.
Rodriguez-Martin B., Alvarez EG., Baez-Ortega A., Zamora J., Supek F., Demeulemeester J., Santamarina M., Ju YS., Temes J., Garcia-Souto D., Detering H., Li Y., Rodriguez-Castro J., Dueso-Barroso A., Bruzos AL., Dentro SC., Blanco MG., Contino G., Ardeljan D., Tojo M., Roberts ND., Zumalave S., Edwards PA., Weischenfeldt J., Puiggròs M., Chong Z., Chen K., Lee EA., Wala JA., Raine KM., Butler A., Waszak SM., Navarro FCP., Schumacher SE., Monlong J., Maura F., Bolli N., Bourque G., Gerstein M., Park PJ., Wedge DC., Beroukhim R., Torrents D., Korbel JO., Martincorena I., Fitzgerald RC., Van Loo P., Kazazian HH., Burns KH., PCAWG Structural Variation Working Group None., Campbell PJ., Tubio JMC., PCAWG Consortium None.
About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.