Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours

Rodriguez-Martin, B.; Alvarez, E. G.; Baez-Ortega, A.; Demeulemeester, J.; Ju, Y. S.; Zamora, J.; Detering, H.; Li, Y.; Contino, G.; Dentro, S. C.; Bruzos, A. L.; Dueso-Barroso, A.; Ardeljan, D.; Tojo, M.; Roberts, N. D.; Blanco, M. G.; Edwards, P. A. W.; Weischenfeldt, J.; Santamarina, M.; Puiggros, M.; Chong, Z.; Chen, K.; Lee, E. A.; Wala, J. A.; Raine, K.; Butler, A.; Waszak, S. M.; Navarro, F. C. P.; Schumacher, S. E.; Monlong, J.; Maura, F.; Bolli, N.; Bourque, G.; Gerstein, M.; Park, P. J.; Berroukhim, R.; Torrents, D.; Korbel, J. O.; Martincorena, I.; Fitzgerald, R. C.; Van Loo, P.; Ka

doi:10.1101/179705

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bioRxiv · 10.1101/179705

Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours

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Abstract

About half of all cancers have somatic integrations of retrotransposons. To characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 37 histological cancer subtypes. We identified 19,166 somatically acquired retrotransposition events, affecting 35% of samples, and spanning a range of event types. L1 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, sometimes removing tumour suppressor genes, as well as inducing 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 in the development of human tumours.

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Rodriguez-Martin, B., Alvarez, E. G., Baez-Ortega, A., Demeulemeester, J., Ju, Y. S., Zamora, J., Detering, H., Li, Y., Contino, G., Dentro, S. C., Bruzos, A. L., Dueso-Barroso, A., Ardeljan, D., Tojo, M., Roberts, N. D., Blanco, M. G., Edwards, P. A. W., Weischenfeldt, J., Santamarina, M., Puiggros, M., Chong, Z., Chen, K., Lee, E. A., Wala, J. A., Raine, K., Butler, A., Waszak, S. M., Navarro, F. C. P., Schumacher, S. E., Monlong, J., Maura, F., Bolli, N., Bourque, G., Gerstein, M., Park, P. J., Berroukhim, R., Torrents, D., Korbel, J. O., Martincorena, I., Fitzgerald, R. C., Van Loo, P., Ka. 2017-08-24. Pan-cancer analysis of whole genomes reveals driver rearrangements promoted by LINE-1 retrotransposition in human tumours. https://doi.org/10.1101/179705

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