A specific signature of radiation therapy–induced DNA deletions was associated with poorer survival.
Major Finding: A specific signature of radiation therapy–induced DNA deletions was associated with poorer survival.
Concept: These genetic signatures implicated classic nonhomologous end joining and APOBEC mutagenesis.
Impact: Understanding these mutation signatures could aid in prognostication and further treatment decisions.
Radiation therapy (RT) causes DNA damage that kills or prevents the replication of cancer cells. Repair of this DNA damage can lead to specific patterns of mutations in tumor cells that survive treatment, but the nature of these mutations and their potential effects on therapy resistance and patient prognosis is not well understood. Using a cohort of matched pre- and posttreatment glioma samples from the GLASS cohort of IDH-mutant tumors, Kocakavuk, Anderson, and colleagues identified an increase of 0.68 small deletions/Mb of DNA (where small deletions included those spanning 5 to 15 bp)in RT-treated samples compared with a median of 0.19 small deletions/Mb in samples not treated with RT, noting the difference to be particularly pronounced in IDH-mutant gliomas. Further analysis of the genomes of the 3,693 genomes from the HMF cohort of metastatic tumors revealed a higher burden of small deletions in RT-treated tumors from patients with a variety of cancer types, including lung, soft tissue or bone, and breast cancer. Analysis of the RT-associated deletions in the GLASS cohort of IDH-mutant gliomas demonstrated a specific genomic signature characterized by longer deletion lengths. This signature was also found in the HMF cohort of metastatic tumors, with a shift toward 5 to 15 bp deletions and away from 1 to 5 bp deletions. An increase in deletions ranging from 20 bp to chromosome-arm length and DNA inversions were also found in RT-treated samples. Further analysis of the RT-associated signatures in both cohorts revealed a strong enrichment of signatures implicated in classic nonhomologous end-joining–mediated DNA repair as well as APOBEC mutagenesis following RT. Stratification of samples from both cohorts into low, intermediate, and high levels of small-deletion burden revealed a correlation with patient survival, with high levels of small deletions correlating with poorer survival, suggesting treatment resistance via efficient RT-induced double-strand break repair. In summary, this work provides new information about the mutations and mutational signatures caused by RT, uncovering a correlation between these and patient clinical outcomes and further supporting the use of radiosensitizers acting via pharmacologic inhibition of DNA repair pathways.
Kocakavuk E, Anderson KJ, Varn FS, Johnson KC, Amin SB, Sulman EP, et al. Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer. Nat Genet 2021 May 27 [Epub ahead of print].
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