Functional Profiling of DNA Repair Pathways in Lung Cancer Patients Uncovers Radiotherapy-Induced and Cancer-Associated Alterations in Oxidative Lesion Repair

DNA repair capacity (DRC), particularly at the pathway level, varies among individuals. While previous studies explored DRC in relation to environmental exposures and cancer risk, few measured DRC in patient-focused cohorts and were focused on one or two repair pathways only. We comprehensively profiled DRC for all the major repair pathways and DNA lesions in 100 lung cancer patients undergoing radiotherapy (RT) using advanced Fluorescence Multiplex based Host Cell Reactivation assays in blood cells before and after RT and investigated how DRC responded to RT and was influenced by clinical variables. Variation between individuals was significant in all pathways and smaller than variation within-person. DNA glycosylase activity decreased immediately following RT and subsequently returned to baseline in patients receiving high-intensity RT during the follow-up months. Lower DRC against oxidative lesions was found in cancer patients compared to healthy controls. These results highlight oxidative DNA damage repair as a sensitive marker of RT response and cancer burden upon profiling the DNA repair landscape.