Monitoring DNA Damage and Repair in Peripheral Blood Mononuclear Cells of Lung Cancer Radiotherapy Patients

Abstract

Thoracic radiotherapy (RT) is required for the curative management of inoperable lung cancer, however, treatment delivery is limited by normal tissue toxicity. Prior studies suggest that using radiation-induced DNA damage response (DDR) in peripheral blood mononuclear cells (PBMC) has potential to predict RT-associated toxicities. We collected PBMC from 38 patients enrolled on a prospective clinical trial who received definitive fractionated RT for non-small cell lung cancer. DDR was measured by automated counting of nuclear γ-H2AX foci in immunofluorescence images. Analysis of samples collected before, during and after RT demonstrated the induction of DNA damage in PBMC collected shortly after RT commenced, however, this damage repaired later. Radiation dose to the tumour and lung contributed to the in vivo induction of γ-H2AX foci. Aliquots of PBMC collected before treatment were also irradiated ex vivo, and γ-H2AX kinetics were analyzed. A trend for increasing of fraction of irreparable DNA damage in patients with higher toxicity grades was revealed. Slow DNA repair in three patients was associated with a combined dysphagia/cough toxicity and was confirmed by elevated in vivo RT-generated irreparable DNA damage. These results warrant inclusion of an assessment of DDR in PBMC in a panel of predictive biomarkers that would identify patients at a higher risk of toxicity.

LncRNA LINC01134 Contributes to Radioresistance in Hepatocellular Carcinoma by Regulating DNA Damage Response via MAPK Signaling Pathway

“…Moreover, the effects of 4 Gy radiation and LINC01134 knockdown rose with radiation time ( Figure 2C ). γ -H2AX foci are reckoned as a biomarker for DNA damage ( Lobachevsky et al, 2020 ). 53BP1 is a DNA damage response factor ( Mirman and de Lange, 2020 ).…”

The DNA damage response network in the treatment of head and neck squamous cell carcinoma

“…Of note, previous studies in solid tumors have shown that monitoring of DDR parameters in the blood may be potentially useful in patient prognosis 53 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 and prediction of treatment response. 52 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 Therefore, a key challenge for our future research is to examine DDR parameters in both tumor biopsies and PBMCs from the same HNSCC patients.…”

A Randomized Feasibility Trial of Stereotactic Prostate Radiation Therapy With or Without Elective Nodal Irradiation in High-Risk Localized Prostate Cancer (SPORT Trial)

“…Levels in lymphocytes peak 30-60 min after irradiation with subsequent rapid decay in an exponential fashion (23). γH2AX foci in circulating lymphocytes following radiotherapy have been studied in lung cancer (24,25) and prostate cancer (26,27) and are associated with radiation dose but correlation with toxicity is less well established.…”