Monitoring DNA Damage and Repair in Peripheral Blood Mononuclear Cells of Lung Cancer Radiotherapy Patients.
Pavel N LobachevskyNicholas W BucknellJoel MasonDiane RussoXiaoyu YinLisa SelbieDavid L BallTomas KronMichael S HofmanShankar SivaOlga A MartinPublished in: Cancers (2020)
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.
Keyphrases
- dna damage
- dna repair
- oxidative stress
- end stage renal disease
- radiation induced
- clinical trial
- dna damage response
- ejection fraction
- chronic kidney disease
- newly diagnosed
- peritoneal dialysis
- radiation therapy
- squamous cell carcinoma
- machine learning
- small cell lung cancer
- randomized controlled trial
- locally advanced
- spinal cord
- risk assessment
- climate change
- single cell
- spinal cord injury
- rectal cancer
- study protocol
- smoking cessation
- replacement therapy
- human health