Mutational signatures of ionizing radiation in second malignancies

Behjati, S. et al. (2016) Mutational signatures of ionizing radiation in second malignancies. Nature Communications, 7(1), 12605. (doi:10.1038/ncomms12605) (PMID:27615322) (PMCID:PMC5027243)

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Abstract

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1–100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cooke, Dr Susie
Authors: Behjati, S., Gundem, G., Wedge, D. C., Roberts, N. D., Tarpey, P. S., Cooke, S. L., Van Loo, P., Alexandrov, L. B., Ramakrishna, M., Davies, H., Nik-Zainal, S., Hardy, C., Latimer, C., Raine, K. M., Stebbings, L., Menzies, A., Jones, D., Shepherd, R., Butler, A. P., Teague, J. W., Jorgensen, M., Khatri, B., Pillay, N., Shlien, A., Futreal, P. A., Badie, C., Cooper, C. S., Eeles, R. A., Easton, D., Foster, C., Neal, D. E., Brewer, D. S., Hamdy, F., Lu, Y.-J., Lynch, A. G., Massi, C. E., Ng, A., Whitaker, H. C., Yu, Y., Zhang, H., Bancroft, E., Berney, D., Camacho, N., Corbishley, C., Dadaev, T., Dennis, N., Dudderidge, T., Edwards, S., Fisher, C., Ghori, J., Gnanapragasam, V. J., Greenman, C., Hawkins, S., Hazell, S., Howat, W., Karaszi, K., Kay, J., Kote-Jarai, Z., Kremeyer, B., Kumar, P., Lambert, A., Leongamornlert, D., Livni, N., Luxton, H., Matthews, L., Mayer, E., Merson, S., Nicol, D., Ogden, C., O’Meara, S., Pelvender, G., Shah, N. C., Tavare, S., Thomas, S., Thompson, A., Verrill, C., Warren, A., Zamora, J., McDermott, U., Bova, G. S., Richardson, A. L., Flanagan, A. M., Stratton, M. R., and Campbell, P. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Nature Communications 7(1):12605
Publisher Policy:Reproduced under a Creative Commons License

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