Journal Article

Mutational signatures of ionizing radiation in second malignancies

Flanagan, Adrienne M., Stebbings, Lucy, Gundem, Gunes, Cooke, Susanna L., Davies, Helen, Futreal, P. Andrew, Pillay, Nischalan, Alexandrov, Ludmil B., Tarpey, Patrick S., Bova, G. Steven, Roberts, Nicola D., Shepherd, Rebecca, Ramakrishna, Manasa, McDermott, Ultan, Behjati, Sam, Butler, Adam P., Richardson, Andrea L., Raine, Keiran M., Jorgensen, Mette, Nik-Zainal, Serena, Hardy, Claire, Wedge, David C., Teague, Jon W., Badie, Christophe, Khatri, Bhavisha, Campbell, Peter J., Shlien, Adam, Latimer, Calli, Menzies, Andy, Van Loo, Peter, Jones, David, Stratton, Michael R.

2016

Overview

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. Ionizing radiation may induce irreparable DNA damage leading to cancer. Here, the authors identify a specific signature of mutations arising in patients exposed to ionizing radiation and suggest that radiation-induced tumorigenesis is associated with higher rates of genome-wide deletions and balanced inversions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/23 / 631/67/2195 / 631/67/69 / Biomarkers / Bone cancer / Breast cancer / Breast Neoplasms / Carcinogens / DNA Damage / Female / Gene Deletion / Genomes / Germ-Line Mutation / Humanities and Social Sciences / Humans / Ionizing radiation / Laboratories / Male / multidisciplinary / Mutation / Neoplasms, Second Primary / Osteosarcoma / Prostate / Prostatic Neoplasms / Radiation therapy / Radiation, Ionizing / Sarcoma / Science / Science (multidisciplinary) / Tumors