期刊
NATURE GENETICS
卷 53, 期 7, 页码 1088-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-021-00874-3
关键词
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资金
- NIH [R01 CA190121, R01 CA237208, R21 NS114873]
- Cancer Center Support Grant [P30 CA034196]
- Musella Foundation
- B*CURED Foundation
- Brain Tumour Charity
- Department of Defense [W81XWH1910246]
- National Cancer Institute [K99 CA226387]
- Jane Coffin Childs Memorial Fund for Medical Research
- American Cancer Society Fellowship [130984-PF-17-141-01-DMC]
- Boehringer Ingelheim Fonds
- German National Academic Foundation
- U.S. Department of Defense (DOD) [W81XWH1910246] Funding Source: U.S. Department of Defense (DOD)
Ionizing radiation induces DNA damage and increases small and large deletions in tumor genomes. Effective repair of radiation-induced DNA damage is associated with worse clinical outcomes, and these genomic changes can be used to predict sensitivity to radiation therapy in recurrent cancer.
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. Radiotherapy induces small and large deletions as well as inversions across the genome in multiple cancer types. The genomic changes associated with radiotherapy correlate with poorer clinical outcomes.
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