Ionizing radiation-induced γ-H2AX activity in whole blood culture and the risk of lung cancer

Abstract

Background: Phenotypic biomarkers of DNA damage repair may enhance cancer risk prediction. The γ-H2AX formed at the sites of double-strand break (DSB) after ionizing radiation is a specific marker of DNA damage.

Methods: In an ongoing case-control study, the baseline and ionizing radiation-induced γ-H2AX levels in peripheral blood lymphocytes (PBL) from frequency-matched 306 untreated patients with lung cancer and 306 controls were measured by a laser scanning cytometer-based immunocytochemical method. The ratio of ionizing radiation-induced γ-H2AX level to the baseline was used to evaluate interindividual variation of DSB damage response and to assess the risk of lung cancer by using unconditional multivariable logistic regression with adjustment of age, sex, ethnicity, smoking status, family history of lung cancer, dust exposure, and emphysema.

Results: The mean γ-H2AX ratio was significantly higher in cases than controls (1.46 ± 0.14 vs. 1.41 ± 0.12, P < 0.001). Dichotomized at the median in controls, high γ-H2AX ratio was significantly associated with increased risk of lung cancer [OR = 2.43; 95% confidence interval (CI): 1.66-3.56]. There was also a significant dose-response relationship between γ-H2AX ratio and lung cancer risk in quartile analysis. Analysis of joint effects with other epidemiologic risk factors revealed elevated risk with increasing number of risk factors.

Conclusion: γ-H2AX activity as shown by measuring DSB damage in ionizing radiation-irradiated PBLs may be a novel phenotypic marker of lung cancer risk.

Impact: γ-H2AX assay is a robust and quantifiable image-based cytometer method that measures mutagen-induced DSB response in PBLs as a potential biomarker in lung cancer risk assessment.

Figure 1

Joint effects of γ-H2AX ratio with smoking status on risk of lung cancer. “Low” referred to subjects with γ-H2AX ratio < median (1.40) of the controls, and “High” referred to subjects with γ-H2AX ratio ≥ median (1.40) of the controls. *Adjusted by age, sex, ethnicity, history of lung cancer, history of dust exposure, and history of emphysema. Numbers in parentheses are the 95% confidence intervals.