This article is important, and should be seen by as many people as possible, as this scientific study will impact greatly the future of our anti-nuclear cause.
By establishing the genetic signatures of any cancer caused by ionizing radiation, any future denial from the nuclear lobby is now impossible. Those scientifically established signatures will also be extremely helpful in court for any future suit from radiation victims.
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.
Exposure to ionizing radiation increases the risk of subsequent cancer. This risk exhibits a strong dose–response relationship, and there appear to be no safe limits for radiation exposure1. This association was first noted by March who observed an increased incidence of leukaemia amongst radiologists2. A leading cause of radiation-induced cancers appears to be exposure to medical radiation, either in the form of radiotherapy for an unrelated malignancy3 or diagnostic radiography4, 5. These iatrogenic tumours arise as de novo neoplasms in a field of therapeutic radiation after a latency period that can span decades6, and are not recurrences of the original cancer7.
Many, but not all, environmental carcinogens induce cancer by increasing the rate of mutation in somatic cells. The physicochemical properties of a given carcinogen govern its interaction with DNA, leading to recurrent ‘signatures’ or patterns of mutations in the genome. These can be reconstructed either from experimental model systems8, 9 or from statistical analyses of cancer genomes in exposed patients10, 11, 12. Ionizing radiation directly damages DNA, and can generate lesions on single bases, single-stranded nicks in the DNA backbone, clustered lesions at several nearby sites and double-stranded DNA breaks13. In experimental systems exposed to radiation, including the murine germline and Arabidopsis thaliana cells, ionizing radiation can cause all classes of mutations, with possible enrichment of indels14, 15, 16, 17, 18, 19, 20, 21, 22. Targeted gene screens in radiation-induced sarcoma have indicated an increased burden of deletions and substitutions with frequent inactivation of TP53 and RB1 (refs 23, 24, 25). In addition, a transcriptome profile that represents a state of chronic oxidative stress has been proposed to be specific to radiation-associated sarcoma26.
We studied the genomes of 12 radiation-associated second malignancies of four different tumour types: osteosarcoma; spindle cell sarcoma; angiosarcoma; breast cancer. These were secondary tumours that arose within a field of therapeutic ionizing radiation and were not thought to be recurrences of the original malignancy treated with radiation. We chose this experimental design for several reasons: the tumours are classic radiotherapy-induced cancers with high attributable risks for the radiation exposure; the radiation exposure occurs over a short time period relative to the evolution of the cancer; and the mutational signatures of sporadic breast cancers and sarcomas have been well documented10, 27, 28, 29. It should be noted that in the absence of biomarkers, a diagnosis of a tumour being radiation-induced cannot be definitively made (see Supplementary Note 1 for clinical details and further discussion).
We subjected these 12 tumours, along with normal tissues from the same patients, to whole-genome sequencing and obtained catalogues of somatic mutations. We compared our findings to 319 radiation-naive breast cancers and sarcomas processed by the same sequencing and bioinformatics pipeline: 251 breast tumours; 33 breast tumours with pathogenic BRCA1 or BRCA2 germline mutations; 35 osteosarcomas (see Methods for cohort details). In addition, we validated our findings in a published series of radiation-naïve and radiation-exposed prostate tumours from ten patients30.
The main aim of our analyses was to search for tumour-type independent, overarching signatures of ionizing radiation. Overall we identified two such signatures in radiation-associative second malignancies, an excess of balanced inversions and of small deletions.
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