Mutational signatures of ionizing radiation in second malignanciesMore about Open Access at the Crick
Authors listSam 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 Teague Mette Jorgensen Bhavisha Khatri Nischalan Pillay Adam Shlien P Andrew Futreal Christophe Badie ICGC Prostate Group Ultan McDermott G Steven Bova Andrea L Richardson Adrienne M Flanagan Michael R Stratton Peter J Campbell ICGC Prostate Group
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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.
Journal Nature Communications