Ionizing radiation causes DNA damage and is a mainstay for cancer treatment, but understanding of its genomic impact is limited. We analyzed mutational spectra following radiotherapy in 190 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis Consortium and 3,693 post-treatment metastatic tumors from the Hartwig Medical Foundation. We identified radiotherapy-associated significant increases in the burden of small deletions (5–15 bp) and large deletions (20+ bp to chromosome-arm length). Small deletions were characterized by a larger span size, lacking breakpoint microhomology and were genomically more dispersed when compared to pre-existing deletions and deletions in non-irradiated tumors. Mutational signature analysis implicated classical non-homologous end-joining-mediated DNA damage repair and APOBEC mutagenesis following radiotherapy. A high radiation-associated deletion burden was associated with worse clinical outcomes, suggesting that effective repair of radiation-induced DNA damage is detrimental to patient survival. These results may be leveraged to predict sensitivity to radiation therapy in recurrent cancer.

电离辐射会导致 DNA 损伤，是癌症治疗的主要手段，但对其基因组影响的了解有限。我们分析了来自神经胶质瘤纵向分析联合会的 190 对原发性和复发性神经胶质瘤和来自 Hartwig 医学基金会的 3,693 例治疗后转移性肿瘤放疗后的突变谱。我们发现放疗相关的小缺失（5-15 bp）和大缺失（20+ bp 到染色体臂长度）的负担显着增加。与预先存在的缺失和未照射肿瘤中的缺失相比，小缺失的特征在于更大的跨度大小、缺乏断点微同源性并且在基因组上更加分散。突变特征分析涉及经典的非同源末端连接介导的 DNA 损伤修复和放疗后的 APOBEC 突变。与辐射相关的高缺失负担与较差的临床结果相关，这表明有效修复辐射引起的 DNA 损伤不利于患者的生存。这些结果可用于预测复发性癌症对放射治疗的敏感性。