Whole-Genome Sequencing Reveals Mutational Signatures Related to Radiation-Induced Sarcomas and DNA-Damage-Repair Pathways

Radiation-induced sarcoma (RIS) is a rare but serious late complication arising from radiotherapy. Despite unfavorable clinical outcomes, the genomic footprints of ionizing radiation in RIS development remain largely unknown. Hence, this study aimed to characterize RIS genomes and the genomic al-terations in them. We analyzed whole-genome sequencing in 11 RIS genomes matched with normal genomes to identify somatic alterations potentially associated with RIS development. Furthermore, the abundance of mutations, mutation signatures, and structural variants in RIS were compared with those in radiation-naive spontaneous sarcomas. The mutation abundance in RIS genomes, including one hypermutated genome, was variable. Cancer-related genes might show different types of genomic alterations. For instance, NF1, NF2, NOTCH1, NOTCH2, PIK3CA, RB1, and TP53 showed singleton somatic mutations; MYC, CDKN2A, RB1, and NF1 showed recurrent copy number alterations; and NF2, ARID1B, and RAD51B showed recurrent structural variations. The genomic footprints of nonhomologous end joining are prevalent at indels of RIS genomes compared with those in spontaneous sarcoma genomes, representing the genomic hallmark of RIS genomes. In addition, frequent chromothripsis was iden-tified along with predisposing germline variants in the DNA-damageerepair pathways in RIS genomes. The characterization of RIS genomes on a whole-genome sequencing scale highlighted that the nonhomologous end joining pathway was associated with tumorigenesis, and it might pave the way for the development of advanced diagnostic and therapeutic strategies for RIS.(c) 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

Automated summary

Radiation-induced sarcoma (RIS) is a rare and serious late complication of radiotherapy. This study analyzed the genomes of 11 RIS tumors and identified somatic alterations potentially associated with RIS development. The results revealed different types of genomic alterations in cancer-related genes and the prevalence of nonhomologous end joining pathway in RIS genomes. The findings provide valuable insights for the diagnosis and treatment of RIS.