Genomic landscape of radiation-induced somatic mutations in a normal cell.

Abstract

Atomic bomb survivors have been found to have an excess risk of late adverse effects, including leukemia, various solid cancers, and non-cancer diseases, depending on the dose of radiation exposure. Radiation-induced DNA damage can lead to errors in DNA repair, resulting in the induction of somatic mutations in cells. Since these mutations are thought to contribute to an increased risk of radiation-induced carcinogenesis, various approaches, such as mutation analysis at specific genetic loci and chromosomal analysis, have been used to investigate their characteristics. However, previous methods were only capable of detecting a subset of radiation-induced mutations, making it difficult to quantitatively and comprehensively capture their specificity, including the mutation spectrum. Recently, whole-genome sequencing combined with of ex vivo single-cell culture has enabled a comprehensive analysis of radiation-induced mutations in individual cells. Such studies, including our own, have demonstrated that short, non-repeat deletions occurring outside of tandem repeats represent the most distinctive signature of radiation-induced mutagenesis, showing clear dose dependence and consistency across multiple tissues. Structural variants (excluding retroelement insertions) and multisite mutations also showed radiation specificity, albeit to a lesser extent and at a lower frequency than non-repeat deletions. These findings may offer insights into the molecular mechanisms underlying radiation-induced oncogenesis and non-cancer disease development.