Low levels of ATM in breast cancer patients with clinical radiosensitivity

Semi-quantitative immuno-blotting provided a reliable and reproducible method to compare levels of the ATM protein for a rare cohort of 20 cancer patients selected on the basis of their severe adverse normal tissue reactions to radiotherapy. We found that 4/12 (33%) of the breast cancer patients with severe adverse normal tissue reactions following radiotherapy had ATM protein levels < 55% compared to the mean for non-reactor controls.ATM mutations are generally considered low risk alleles for breast cancer and clinical radiosensitivity. From results reported here we propose a tentative ATM protein threshold of ~55% for high-risk of clinical radiosensitivity for breast cancer patients.Primary treatment for organ-confined breast cancer usually involves a combination of limited breast-conservation surgery and radiotherapy yielding control rates equivalent to mastectomy. Such radiotherapy is usually tolerated well except for the very small percentage of patients who experience severe adverse normal tissue reactions (RTOG3-4 reactions) [1]. There is little empirical evidence to support anecdotal reports of clinical radiosensitivity in connective tissue disorders including systemic lupus erythematosus (SLE) [2-5]. However, other genetic predispositions, including autosomal recessive ataxia telangiectasia (A-T), have a clear association with clinical radiosensitivity [6,7]. A-T is an autosomal recessive disorder characterised by early-onset neurodegeneration, oculocutaneous telangiectasia, immunodeficiency, hypogonadism, cancer susceptibility and acute hypersensitivity to radiotherapy [6]. ATM, the susceptibility gene for A-T, encodes a protein kinase activated in response to ionising radiation (IR) induced DNA double-strand breaks that facilitates the phosphorylation of numerous molecular intermediates involved in cell-cycle regulation and DNA repair. A-T patients usually harbour compound ATM mutations comprising either two non-allelic null mutations or one null and one