Early marker of DNA damage response, ATM, as a predictor of clinical outcome following radiotherapy in rectal cancer patients

Background: Ataxia telangiectasia mutated (ATM) is a key protein involved in DNA damage repair following double strand breaks and is important in maintaining genomic stability. Altered expression in rectal cancer cells may affect the ability of tumour cells to recover following exposure to ionizing radiation. Thus, we aimed to ascertain the relationship between ATM expression patterns in rectal cancer cells with radiosensitivity and survival outcomes. Methods: 263 rectal cancer specimens, including 54 patients who received preoperative radiotherapy, were immunohistochemically stained for ATM. Expression patterns were scored separately in cancer cells retrieved from the centre and periphery of the tumour, and compared with clinicohistopathological data, tumour regression grade (TRG) and disease-free and overall survival. Results: Negative ATM expression in tumour periphery cells correlated with older age (p=0.013) and lower grade (p=0.044), and predicted greater radiotherapy response as measured by TRG (p=0.036). Negative ATM expression in tumour periphery cells was also associated with longer disease-free survival [HR=2.951 (1.128−7.723), p=0.028]. Subset analysis in patients who received preoperative radiotherapy showed a similar trend towards longer disease-free survival [HR=7.206 (0.959-54.123), p=0.055]. Negative ATM expression in tumour centre cells was associated with longer overall survival [HR=2.117 (1.070−4.188), p=0.031]. Conclusions: ATM is a potential predictive and prognostic biomarker for radiosensitivity, disease-free and overall survival in patients with rectal cancer. Furthermore, it may facilitate the identification of patients who would benefit from preoperative radiotherapy.