Mutational spectrum of ionizing radiation in mammalian cells

Abstract

Ionizing radiation (IR) is a well-known carcinogen to induce nearly all types of cancer. Conventional cytogenetic and sequencing studies revealed that IR generates various types of DNA damages including single nucleotide variations and double strand breaks (DSBs). However, IR-induced mutagenesis has not been comprehensively explored in the era of next generation sequencing whereas mutational signatures of other endogenous and exogenous mutagenic process have been newly uncovered. Here, I performed 156 whole genome sequences of single-cell derived clonal organoid lines established from 8 different cell types: 98 irradiated (≥1Gy) and 58 controls. Balanced inversions, balanced translocations and simple large deletions were highly specific in irradiated organoids. In >30% of irradiated organoids, I observed at least 1 complex genomic rearrangements (CGRs) including chromoplexy, chromothripsis and breakage-fusion-bridge events. Through careful examination of their rearrangement breakpoints and patterns, I was able to reconstruct the step-by-step processes in the CGR formations. Furthermore, using a total of 1430 genomic rearrangements identified from all the lines, I revealed the IR-associated mutational signatures which provide deep insights into the DNA damage and repair processes of our cells against IR-mediated crisis. In addition to the structural variations, double base substitutions and non-repetitive small insertions and deletions (indels) were observed more frequently in irradiated samples. To my knowledge, this study provides the first comprehensive IR-mediated mutational signatures in normal cells. Most intriguingly, this findings clearly demonstrate that rearrangement bursts can be triggered by IR. Our results indicate that a fraction of fusion oncogenes, for example, EML4-ALK and KIF5B-RET found in lung adenocarcinomas, can be stochastically acquired by environmental IR exposure early in lifetime.