Validating Radiosensitivity with Pre-Exposure Differential Gene Expression in Peripheral Blood Predicting Survival...

Area of Science:

• Radiation Biology
• Genomics
• Primate Models

Background:

• Individual radiosensitivity varies significantly, yet the underlying genetic factors remain largely unknown.
• Previous studies identified eight genes associated with survival in rhesus macaques post-radiation.
• Understanding these genetic variations is crucial for predicting radiation response and developing countermeasures.

Purpose of the Study:

• To validate previously identified gene expression (GE) biomarkers for predicting survival after radiation exposure in a second cohort of rhesus macaques.
• To investigate the association of CHD5 gene expression levels with survival outcomes following different radiation doses and treatments.

Main Methods:

• Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to measure gene expression in peripheral blood samples from two rhesus macaque cohorts.
• Cycle threshold (Ct) values for selected genes, including CHD5, were normalized to 18S rRNA and analyzed for association with survival up to 60 days post-irradiation.
• Logistic regression and receiver operating characteristic (ROC) curve analyses were employed to assess predictive values of gene expression for survival.

Main Results:

• Two genes, CHD5 and CHI3L1, showed significant association with survival in the validation cohort.
• Only CHD5 exhibited consistent expression changes in the same direction across both cohorts, indicating its potential as a radiosensitivity biomarker.
• Pre-radiation CHD5 expression levels, specifically low copy numbers (Ct ≤ 11), were significantly associated with increased mortality in males (P = 0.01), while high copy numbers (Ct ≥ 14.4) were linked to survival.

Conclusions:

• The study identified distinct subsets of male rhesus macaques with high or low pre-radiation CHD5 gene expression, capable of predicting survival outcomes.
• CHD5 gene expression serves as a potential predictive biomarker for radiosensitivity and survival in male nonhuman primates, independent of radiation dose, sex, or treatment.
• Further research into CHD5's role in DNA damage response and proliferation control could elucidate mechanisms of radiation resistance.