Mutational signatures of ionizing radiation in second malignancies

Behjati, Sam, Gundem, Gunes, Wedge, David C., Roberts, Nicola D., Tarpey, Patrick S., Cooke, Susanna L., Van Loo, Peter, Alexandrov, Ludmil B., Ramakrishna, Manasa, Davies, Helen, Nik-Zainal, Serena, Hardy, Claire, Latimer, Calli, Raine, Keiran M., Stebbings, Lucy, Menzies, Andy, Jones, David, Shepherd, Rebecca, Butler, Adam P., Teague, Jon W., Jorgensen, Mette, Khatri, Bhavisha, Pillay, Nischalan, Shlien, Adam, Futreal, P. Andrew, Badie, Christophe, Cooper, Colin S., Eeles, Rosalind A., Easton, Douglas, Foster, Christopher, Neal, David E., Brewer, Daniel S., Hamdy, Freddie, Lu, Yong-Jie, Lynch, Andrew G., Massi, Charlie E., Ng, Anthony, Whitaker, Hayley C., Yu, Yongwei, Zhang, Hongwei, Bancroft, Elizabeth, Berney, Dan, Camacho, Niedzica, Corbishley, Cathy, Dadaev, Tokhir, Dennis, Nening, Dudderidge, Tim, Edwards, Sandra, Fisher, Cyril, Ghori, Jilur, Gnanapragasam, Vincent J., Greenman, Christopher, Hawkins, Steve, Hazell, Steven, Howat, Will, Karaszi, Katalin, Kay, Jonathan, Kote-Jarai, Zsofia, Kremeyer, Barbara, Kumar, Pardeep, Lambert, Adam, Leongamornlert, Daniel, Livni, Naomi, Luxton, Hayley, Matthews, Lucy, Mayer, Erik, Merson, Susan, Nicol, David, Ogden, Christopher, O’Meara, Sarah, Pelvender, Gill, Shah, Nimish C., Tavare, Simon, Thomas, Sarah, Thompson, Alan, Verrill, Claire, Warren, Anne, Zamora, Jorge, McDermott, Ultan, Bova, G. Steven, Richardson, Andrea L., Flanagan, Adrienne M., Stratton, Michael R. and Campbell, Peter J. (2016) Mutational signatures of ionizing radiation in second malignancies. Nature Communications, 7. ISSN 2041-1723

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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: Article
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Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Computing Sciences

University of East Anglia > Faculty of Science > Research Groups > Computational Biology (subgroups are shown below) > Analysis and models of genomic variation
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Depositing User: Pure Connector
Date Deposited: 26 Sep 2016 10:00
Last Modified: 17 Mar 2020 22:25
URI: https://ueaeprints.uea.ac.uk/id/eprint/60579
DOI: 10.1038/ncomms12605

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