Journal Article

Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer

Kocakavuk, Emre, Johnson, Kevin C., Varn, Frederick S., Amin, Samirkumar B., Anderson, Kevin J., Verhaak, Roel G. W., Barthel, Floris P., Lolkema, Martijn P., Sulman, Erik. P.

2021

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/212 / 631/67/1059/485 / 631/67/1922 / 692/700/565/485 / Agriculture / Analysis / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Brain tumors / Cancer / Cancer Research / Cancer therapies / Care and treatment / Clinical outcomes / Complications and side effects / Consortia / Deletion / Deoxyribonucleic acid / DNA / DNA damage / DNA Damage - radiation effects / DNA repair / Gene Function / Genetic aspects / Genomes / Glioma / Health aspects / Health services / Homology / Human Genetics / Humans / Impact analysis / Ionizing radiation / Metastases / Metastasis / Mutagenesis / Mutagenesis - radiation effects / Mutation / Neoplasm Recurrence, Local / Neoplasms - epidemiology / Neoplasms - genetics / Neoplasms - mortality / Neoplasms - radiotherapy / Non-homologous end joining / Patient outcomes / Patients / Prognosis / Radiation damage / Radiation effects / Radiation therapy / Radiation, Ionizing / Radiotherapy / Radiotherapy - adverse effects / Regression analysis / Repair / Sequence Deletion - radiation effects / Signature analysis / Tumors