New insights into patient radiosensitivity in relation to the biology of the ATM protein

The cloning of the mutated in ataxia-telangiectasia (ATM) gene in 1995 led to major insights into the biology of ATM and axiomatically into the role of cell signaling in the DNA damage response (DDR) network and its importance for cellular radiosensitivity. Although individuals afflicted with DDR-related defects such as ATM are extremely radiosensitive, the goal of using information on the status of such genes in the context of an individual cancer patient’s risk of experiencing normal tissue complications if they were to receive radiation therapy (XRT) remains largely unfulfilled. However, two separate studies published in 2016 and relating to very different aspects of ATM biology show great promise for application to this scenario. One of these [Andreassen et al. Radiother Oncol 2016 Jul 18. pii: S0167-8140(16)31177-X], a radiogenomics approach, showed that a single nucleotide polymorphism in the ATM gene, specifically ATM G>A Asp1853Asn (rs1801516), is significantly associated with the risk of both acute and late complications when applied to a large cohort of cancer patients. The second study (Granzotto et al. Int J Radiat Oncol Biol Phys 2016; 94: 450-60), which used a cellular phenotype approach, showed that the combination of readouts for DNA double strand break (DSB) recognition (peak early levels of phosphorylated nuclear ATM foci) and DSB repair (residual γH2AX foci after 24 h) in 2 Gy-irradiated fibroblasts also provided a powerful discrimination of individual patient radiosensitivity, including a clear demarcation between the two sub-sets of hyper-radiosensitivity that comprise grade 4–5 responses, namely ATM-like with defects in both DSB recognition and repair, and those related to severe DSB-repair defects (such as in Ligase IV syndrome). These encouraging findings suggest that we may be getting close to realizing predictive assays that will give clinicians a reasonable insight into the radiation sensitivity of an individual patient.