Validation of the cell cycle G2 delay assay in assessing ionizing radiation sensitivity and breast cancer risk

Genetic variations in cell cycle checkpoints and DNA repair genes are associated with prolonged cell cycle G2 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 G2 delay index, %G2–M, G2/G0–G1, and (G2/G0–G1)/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 G2 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 G2 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 G2 delay and breast cancer risk. The cell cycle G2 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

Nucleotide-excision repair and prostate cancer risk

Prostate cancer (CaP) is the most commonly diagnosed nonskin cancer and the second leading cause of cancer death in American men. Its etiology is not fully understood. Ethnicity/race and family history are associated with it, and incidence increases with age. As with other solid tumors, accumulation of mutations and decline in DNA repair during aging may lead to CaP. However, we believe that conducting a large population screening for every cancer susceptibility gene (e.g. DNA repair) is only meaningful, if we can predict to what extent genetic variants contribute to DNA-repair functional phenotype and CaP risk. This review focuses on the association between CaP and nucleotide excision repair (NER), because some of the DNA adducts generated by CaP-related carcinogens are removed by the NER pathway, and our previous data showed a significant association between lower NER capacity (NERC) and CaP risk. Many laboratories, including ours, have employed a variety of approaches to evaluate the functional significance of DNA-repair single-nucleotide polymorphisms (SNPs) in human cancer risk assessment. Genetic profiling and computational modeling that can predict NERC may have great potential for CaP-risk assessment, because the current NERC assay is quite labor intensive, costly, and therefore not suitable for population-based screening