Radiotherapy of diffuse gliomas results in an increased number of genomic small deletions that make up a unique signature, according to findings presented at the MAP 2020 Virtual Congress. Furthermore, an increased burden of radiation-induced deletions was significantly associated with poorer patient outcome.
Emre Kocakavuk of the Jackson Laboratory for Genomic Medicine in Farmington, USA headed a research team that endevoured to determine the genomic effects of radiation therapy, which remain unknown. In contrast, it is known that alkylating chemotherapy can drive tumours to develop a hypermutator phenotype.
The investigators analysed the mutational spectra following treatment with ionizing radiation in sequencing data from 190 paired primary and recurrent gliomas from the Glioma Longitudinal Analysis (GLASS) dataset and 2116 post-treatment metastatic tumours from the Hartwig Medical Foundation.
A significant increase in the burden of small deletions was identified after radiation therapy that was independent of other factors. These novel deletions demonstrated distinct characteristics when compared with pre-existing deletions present prior to radiation therapy and also compared with deletions in radiation-untreated tumours.
In comparison, the radiation therapy-acquired deletions characteristically had a larger deletion size; the GLASS cohort (p = 1.2e-02) and the metastatic cohort (p < 2e-16 by Mann-Whitney U test), and an increased distance to repetitive DNA elements (p < 2e-16, by Kolmogorov-Smirnov test). A reduction in microhomology at breakpoints (p = 3.2e-02, paired Wilcoxon signed-rank test) was also detected.
The investigators explained that these observations suggested that canonical non-homologous end joining (c-NHEJ) was the preferred pathway for DNA double-strand break repair of radiation therapy-induced DNA damage. In addition, radiotherapy resulted in frequent chromosomal deletions and significantly increased frequencies of CDKN2A homozygous deletions in IDH-mutant gliomas.
Importantly, a high burden of radiation therapy-associated deletions was found to associate with poorer clinical outcomes; GLASS cohort (p < 1e-04), and metastatic cohort (p = 2.6e-02, by Wald test).
According to the authors, these findings suggest that effective repair of radiation therapy-induced DNA damage is detrimental to patient survival. They further suggest that inhibiting c-NHEJ may be a viable strategy for improving the anti-tumour effect of radiotherapy.
Taken together, the identified genomic scars resulting from radiation therapy reflect a more aggressive tumour with increased levels of resistance to subsequnt treatments.
This work was supported by multiple grants.
2MO – Kocakavuk E, Anderson KJ, Johnson KC, et al. Radiotherapy in cancer is associated with a deletion signature that contributes to poor patient outcomes. MAP 2020 Virtual Congress (9-10 October 2020).