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Mutational Signatures in Radiation-Induced Cancer: A Review of Experimental Animal and Human Studies
by
,
Kazuhiro Daino
1,*
,
Chizuru Tsuruoka
1,
Atsuko Ishikawa
1,
Shizuko Kakinuma
1,2 and
Tatsuhiko Imaoka
1 1
Department of Radiation Effects Research, Institute for Radiological Science, National Institutes for Quantum Science and Technology (QST), Chiba 263-8555, Japan
2
Department of Radiobiology, Institute for Environmental Sciences (IES), Aomori 039-3212, Japan
*
Author to whom correspondence should be addressed.
Biology 2025, 14(9), 1142; https://doi.org/10.3390/biology14091142
Submission received: 15 July 2025
/
Revised: 27 August 2025
/
Accepted: 28 August 2025
/
Published: 29 August 2025
(This article belongs to the Special Issue Radiation and Biology: Investigating Cellular, Organismal, and Environmental Responses)
Simple Summary
Ionizing radiation can lead to breaks in the double-stranded structure of DNA. Although cells have mechanisms that can repair such breaks, misrejoining events can occur that lead to mutations in an individual’s genome. When mutations affect certain genes, such as oncogenes and tumor-suppressor genes, cancer can result. Although ionizing radiation is a known cause of cancer, it has been difficult to determine how much of an excess cancer risk results from low-dose radiation exposure. Radiation signatures that distinguish radiation-induced cancers from spontaneous cancers are thus useful for assessing cancer risks after exposure to low-dose radiation. Recent advances in high-throughput sequencing technologies have enabled the comprehensive profiling of mutations in individual cancer cells. Analyses of radiation-associated cancer genomes have identified an increase in small deletions and chromosome rearrangements, including large deletions, inversions, and translocations, which are likely to be formed by the misrejoining of DNA double-strand breaks. Among these, chromosome rearrangements leading to cancer-related mutational events are potentially useful as biomarkers and as therapeutic targets for treating radiation-induced cancer. This review summarizes research on radiation-induced mutational signatures found in animal and human cancers, consolidates current knowledge, and discusses the future perspectives in this research field.
Abstract
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.
