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Thu Sep 15, 2016, 01:47 PM

ionizing radiation generates distinctive mutational signatures

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 1100 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.


Mutational signatures of ionizing radiation in second malignancies
Sam Behjati, Gunes Gundem[]Peter J. Campbell
Nature Communications 7, Article number: 12605 (2016)
doi:10.1038/ncomms12605
Open Access http://www.nature.com/articles/ncomms12605

Discussion
Overall we identified two genomic imprints of ionizing radiation, an excess of deletions and of an exceedingly rare type of rearrangement, balanced inversions. The validity of our study may be limited by the overall number of tumours we examined and the small number of each tumour type. Yet it would seem unlikely that the enrichment in radiation-associated tumours of deletions and of balanced inversions occurred by chance. This view is supported by our statistical analyses as well as the fact that the signatures were tumour-type independent. Both signatures were present across four different tumour types and could be validated in a cohort of radiation-exposed prostate cancer lesions, despite differences in the biological context of radiation-exposed prostate tumours and radiation-associated second malignancies (Supplementary Note 2). Particularly striking is patient PD11331 whose primary prostate lesion was irradiated after metastases had formed. The primary lesion, but not the metastases, exhibited the genomic features of ionizing radiation.

The relatively low number of mutations that we directly linked to ionizing radiation may seem surprising for such a well-known carcinogen. It is certainly considerably less than seen for cancers associated with tobacco, sunlight or aristolochic acid exposure10. This probably reflects the fact that although the attributable risk of such cancers is high, the absolute risk is relatively low. For example, >90% of angiosarcomas occurring after radiotherapy for primary breast cancer are attributable to radiation, but only one in a thousand women receiving such radiotherapy will develop angiosarcomas37, with a latency of many years. This suggests that although ionizing radiation clearly pushes bystander cells in the radiotherapy field towards cancer, the absolute burden of radiation-induced mutations per cell would not be high and additional driver mutations would be required.

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