title: Validation of the cell cycle G(2) delay assay in assessing ionizing radiation sensitivity and breast cancer risk.
abstract: Genetic variations in cell cycle checkpoints and DNA repair genes are associated with prolonged cell cycle G(2) delay following ionizing radiation (IR) treatment and breast cancer risk. However, different studies reported conflicting results examining the association between post-IR cell cycle delay and breast cancer risk utilizing four different parameters: cell cycle G(2) delay index, %G(2)-M, G(2)/G(0)-G(1), and (G(2)/G(0)-G(1))/S. Therefore, we evaluated whether different parameters may influence study results using a data set from 118 breast cancer cases and 225 controls as well as lymphoblastoid and breast cancer cell lines with different genetic defects. Our results suggest that cell cycle G(2) delay index may serve as the best parameter in assessing breast cancer risk, genetic regulation of IR-sensitivity, and mutations of ataxia telangiectasia mutated (ATM) and TP53. Cell cycle delay in 21 lymphoblastoid cell lines derived from BRCA1 mutation carriers was not different from that in controls. We also showed that IR-induced DNA-damage signaling, as measured by phosphorylation of H2AX on serine 139 (γ-H2AX) was inversely associated with cell cycle G(2) delay index. In summary, the cellular responses to IR are extremely complex; mutations or genetic variations in DNA damage signaling, cell cycle checkpoints, and DNA repair contribute to cell cycle G(2) delay and breast cancer risk. The cell cycle G(2) delay assay characterized in this study may help identify subpopulations with elevated risk of breast cancer or susceptibility to adverse effects in normal tissue following radiotherapy.
authors.affiliation: Sylvester Comprehensive Cancer Center.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Hill
authors.forename: Kristina
authors.initials: K
authors.lastname: Tansavatdi
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Lockett
authors.forename: Glenn O
authors.initials: GO
authors.lastname: Allen
authors.forename: Cristiane
authors.initials: C
authors.lastname: Takita
authors.forename: Alan
authors.initials: A
authors.lastname: Pollack
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hu