Radiation-Induced Genetic Deletions May Be Associated With Poorer Patient Outcomes

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Treatment of diffuse gliomas with radiotherapy resulted in an increased number of genomic small deletions that make up a unique signature, according to findings presented at the Molecular Analysis for Precision Oncology (MAP) Congress 2020 (Abstract 2MO). Furthermore, an increased burden of radiation-induced deletions was significantly associated with poorer patient outcomes.

A research team set up the study to determine the genomic effects of radiation therapy, which remain unknown. In contrast, it is known that alkylating chemotherapy can drive tumors to develop a hypermutator phenotype.

Study Methods, Burden Discovery

The investigators analyzed the mutational spectra following treatment with ionizing radiation in sequencing data from 190 paired patients with primary and recurrent gliomas from the Glioma Longitudinal Analysis (GLASS) dataset, and 2,116 posttreatment metastatic tumors 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 that were present prior to radiation therapy and also compared with deletions in tumors that were not treated with radiation.

In comparison, the radiation therapy–acquired deletions characteristically had a larger deletion size (the GLASS cohort, P = 1.2e-02; 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 nonhomologous end-joining 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.

A high burden of radiation therapy–associated deletions was associated with poorer clinical outcomes (GLASS cohort, P < 1e-04; 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 canonical nonhomologous end-joining may be a viable strategy for improving the antitumor effect of radiotherapy.

Taken together, the identified genomic scars resulting from radiation therapy reflect a more aggressive tumor with increased levels of resistance to subsequent treatment.

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