Identification of the mutation signature of the cancer genome caused by irradiation

Abstract

Background and purpose: Ionising radiation causes mutations in the genomes of tumour cells and serves as a potent treatment for cancer. However, the mutation signatures in the cancer genome following ionising radiation have not been documented.

Materials and methods: We established an in vitro experimental system to analyse the presence of de novo mutations in the cancer genome of irradiated (60 Gy/20 fr/4 weeks) oesophageal cancer cell lines. Subsequently, we performed whole-genome, chromatin immunoprecipitation, and RNA sequencing using untreated and irradiated samples to assess the damage to the genome caused by radiation and understand the underlying mechanism.

Results: The irradiated cancer cells exhibited hotspots for the de novo 8502-12966 single nucleotide variants and 954-1,331 indels on the chromosome. These single nucleotide variants primarily originated from double-stranded break repair errors, as determined using mutation signature analysis. The hotspots partially overlapped with the sites of H3K9 trimethylation, which are regions characterised by a weak capacity for double-stranded break repair.

Conclusion: This study highlights the signature and underlying mechanism of radiation on the cancer genome.

Keywords: Cancer genome; Irradiation; Mutation hot spot; Mutation signature; Radiotherapy; Whole genome sequence.