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

Abstract

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 (P¼3e-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 RTuntreated tumors. Radiation therapy-acquired deletions were characterized by a larger deletion size (GLASS and HMF, P¼1.5e-04 and P¼6e-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 ¼ 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 (P¼1.9e-05, Fisher's exact test). Finally, a high burden of RT-associated deletions was associated with worse clinical outcomes (GLASS and HMF, P¼3.4e-02 and P<1e-04, respectively; log-rank test).