Persistence of Gamma-H2AX Foci in Irradiated Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice

The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in their ability to efficiently repair DNA double strand breaks resulting from radiation exposure. We phenotyped mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA double strand breaks during protracted radiation exposures. We monitored persistent gamma-H2AX radiation induced foci (RIF) 24 hours after exposure to chronic gamma-rays as a surrogate marker for repair deficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/cHeN founder strain. We observed a very strong correlation R2 = 79.18%, P < 0.001) between the level of persistent RIF and radiogenic lung cancer percent incidence measured in the same strains. Interestingly, spontaneous levels of foci in non-irradiated strains also showed good correlation with lung cancer incidence (R2=32.74%, P =0.013). These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains and that high levels of spontaneous DNA damage is also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that such phenotyping assay could be used to detect radiogenic lung cancer susceptibility in humans.