ATM Haplotypes and Cellular Response to DNA Damage: Association with Breast Cancer Risk and Clinical Radiosensitivity

The ATM gene, mutated in the cancer-prone and radiation-sensitive syndrome ataxia-telangiectasia (AT), could predispose to breast cancer (BC) development and adverse radiotherapy responses. Sixteen ATM variants were genotyped in 254 BC cases, 70 of whom were adverse radiotherapy responders (RS-BC), and 312 control subjects and the ATM haplotypes were constructed. Constitutive ATM protein, cell survival, and the p53 response after exposure to ionizing radiation were compared in lymphoblastoid cell lines (LCLs) established from the BC cases, AT, and normal individuals. The tightly linked intronic ATM polymorphisms IVS22-77 T>C and IVS48 + 238 C>G, in the homozygote state were associated with increased BC risk [IVS22-77 CC versus TT odds ratio (OR), 1.67; 95% confidence interval (CI), 1.00-2.81], and in the heterozygote state with clinical radioprotection (IVS22-77 CT versus TT OR, 0.45; 95% CI, 0.24-0.85). Homozygote carriers of the G5557A variant were over-represented in RS-BC cases compared with non-RS-BC cases (OR, 6.76; 95% CI, 1.19-38.43). These three single nucleotide polymorphisms were associated with the three major ATM haplotypes present in >80% of the study population. BC LCLs treated with ionizing radiation exhibited an intermediate cell survival and p53 response between that of normal and AT LCLs, with the response in the RS-BC LCLs being more compromised than in the non-RS-BC LCLs. Our study suggests a general pattern of increased BC risk associated with carrying any one of the ATM variants studied, with a significant association being observed in individuals carrying variants on both ATM alleles (OR, 1.75; 95% CI, 1.09-2.81) and that ATM variants may impact on radiation sensitivity.