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

• Published in: Radiotherapy and oncology Vol. 155; pp. 10 - 16
• Main Authors: Kageyama, Shun-Ichiro, Du, Junyan, Kaneko, Syuzo, Hamamoto, Ryuji, Yamaguchi, Shigeo, Yamashita, Riu, Okumura, Masayuki, Motegi, Atsushi, Hojo, Hidehiro, Nakamura, Masaki, Tsuchihara, Katsuya, Akimoto, Tetsuo
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.02.2021
• Subjects: Cancer genome; DNA Repair - genetics; Humans; Irradiation; Mutation; Mutation hot spot; Mutation signature; Neoplasms - genetics; Neoplasms - radiotherapy; Radiation, Ionizing; Radiotherapy; Whole genome sequence; Irradiation; Mutation signature; Whole genome sequence; Radiotherapy; Cancer genome; Mutation hot spot
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2020.10.020

[Display omitted] •Sequencing showed de novo mutations in irradiated oesophageal cancer cells.•Irradiated cells had hotspots for single nucleotide variants and indels.•Single nucleotide variants originated from errors in double-stranded break repair.•Mutation profiles of irradiated cells will help understand the cancer genome.•Mutations signatures may help devise radio- and combination therapy for cancers. 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. 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. 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. This study highlights the signature and underlying mechanism of radiation on the cancer genome.