Mutational signatures of ionizing radiation in second malignancies

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

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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.
Original languageEnglish
Article number12605
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 12 Sep 2016

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