Abstract
BACKGROUND: Telomere shortening is a biomarker for genome instability and aging, and the vulnerability of telomeric DNA to oxidative damage suggests its potential role in mediating radiotherapy (RT) side effects. This study evaluates telomere length (TL) as a biomarker for clinical radiosensitivity and adverse outcomes in thoracic RT-treated patients.
METHODS: Cancer patients receiving thoracic RT (2019-2022) were prospectively enrolled at [Anonymized for Review]. Peripheral blood mononuclear cells (PBMCs) were collected pre-RT and up to 12 months post-RT. TL was measured using quantitative PCR, and multi-pathway DNA repair capacity (DRC) was simultaneously assessed by fluorescence multiplex host cell reactivation (FM-HCR) assays. RT outcomes included patient-reported quality of life and radiation pneumonitis. Linear mixed-effects models were used to analyze TL dynamics; risk prediction models for RT outcomes were evaluated using area under the curve.
RESULTS: Pre-RT TL decreased with age (0.44% lower per year, 95% CI: 0.12%, 0.77%) and advanced cancer stage (6.87% lower per step increase of stage, 95% CI: 3.45%, 10.16%). Radical RT was associated with telomere shortening (3.7% lower, 95% CI: 0.27%, 7.07%) in PBMCs, detectable up to 6 months post-RT. Pre-RT TL strongly predicted post-RT changes, and TL dynamics outperformed static measures in predicting symptom burden and radiation pneumonitis. Positive associations were observed between TL and DRC against oxidative lesions, with A:8oxoG repair capacity mediating 12.8% of RT-induced TL shortening.
CONCLUSIONS: Lymphocyte TL can reflect individual radiosensitivity and interact with oxidative damage repair. Longitudinal assessment of TL dynamics provides additional predictive value for adverse RT outcomes compared to static measures. Further studies are needed to fully determine the clinical utility of TL.