340O - Radiotherapy is associated with deletion signatures that contribute to poor survival outcomes in cancer patients

Background

Diffuse gliomas are highly aggressive brain tumors that invariably relapse despite treatment with chemo- and radiotherapy. Treatment with alkylating chemotherapy can drive tumors to develop a hypermutator phenotype. In contrast, the genomic effects of radiotherapy (RT) remain unknown.

Methods

We analyzed the mutational spectra following treatment with RT in whole genome or exome sequencing data from over > 4,000 samples, including 190 paired primary-recurrent gliomas from the Glioma Longitudinal Analysis (GLASS) dataset and 3693 post-treatment metastatic tumors from the Hartwig Medical Foundation.

Results

We identified a significant increase in the burden of small deletions following radiation therapy that was independent of other factors (P=3e-03, log-linear regression model). These novel deletions demonstrated distinct characteristics when compared to pre-existing deletions present prior to RT-treatment and deletions in RT-untreated tumors. Radiation therapy-acquired deletions were characterized by a larger deletion size (GLASS and HMF, P=1.5e-04 and P=6e-16, respectively; Mann-Whitney U test), an increased distance to repetitive DNA elements (P<2.2e-16, Kolmogorov-Smirnov test) and a lack of microhomology at breakpoints (P = 6.6e-05, paired Wilcoxon signed-rank test).

These observations suggested that canonical non-homologous end joining (c-NHEJ) was the preferred pathway for DNA double strand break repair of RT-induced DNA damage. Furthermore, radiotherapy resulted in frequent chromosomal deletions and significantly increased frequencies of CDKN2A homozygous deletions in IDHmut glioma (P=1.9e-05, Fisher’s exact test). Finally, a high burden of RT-associated deletions was associated with worse clinical outcomes (GLASS and HMF, P=3.4e-02 and P<1e-04, respectively; log-rank test).

Conclusions

Our results collectively suggest that effective repair of RT-induced DNA damage is detrimental to patient survival and that inhibiting c-NHEJ may be a viable strategy for improving the cancer-killing effect of radiotherapy. Taken together, the identified genomic scars as a result of radiation therapy reflect a more aggressive tumor with increased levels of resistance to follow up treatments.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

NIH.

Disclosure

All authors have declared no conflicts of interest.