Mutational Signatures in Radiation-Induced Cancer: A Review of Experimental Animal and Human Studies

Ionizing radiation can damage DNA, leading to mutations, and is a risk factor for cancer. Based on the assumption that all radiation exposure poses a risk in linear proportion to its dose, ionizing radiation is considered a non-threshold carcinogen. However, most epidemiological studies have had insufficient statistical power to detect excess cancer risks from low-dose radiation exposure. Therefore, research is needed to identify radiation signatures that distinguish radiation-induced cancers from spontaneously developed cancers. In rodent cancer models, interstitial chromosomal deletions of specific tumor-suppressor gene loci are characteristically found in cancers from irradiated animals. In humans, a high frequency of small deletions and chromosome rearrangements, such as large deletions, inversions, and translocations, has also been reported in second cancers that develop in patients who received radiotherapy and in thyroid cancers diagnosed in residents after the Chornobyl accident. These genomic alterations are likely to be generated as a consequence of the processing of radiation-induced DNA double-strand breaks. Particularly, chromosome rearrangements that occur at loci directly linked to tumor formation after ionizing-radiation exposure are potentially useful as biomarkers and as therapeutic targets for radiation-induced cancer. Here we provide an overview of the radiation-induced mutational signatures observed in animal and human cancers.