HETEROZYGOSITY FOR MUTATIONS IN THE ATAXIA-TELANGIECTASIA GENE IS NOTA MAJOR CAUSE OF RADIOTHERAPY COMPLICATIONS IN BREAST-CANCER PATIENTS

Of patients being treated by radiotherapy for cancer, a small proporti on develop marked long-term radiation damage, It is believed that this is due, at least in pall, to intrinsic individual differences in radi osensitivity, but the underlying mechanism is unknown. Individuals aff ected by the recessive disease ataxia telangiectasia (AT) exhibit extr eme sensitivity to ionizing radiation. Cells from such individuals are also radiosensitive in in vitro assays, and cells from AT heterozygot es are reported to show in vitro radiosensitivity at an intermediate l evel between homozygotes and control subjects. In order to examine the possibility that a defect in the ATM gene may account for a proportio n of radiotherapy complications, 41 breast cancer patients developing marked changes in breast appearance after radiotherapy and 39 control subjects who showed no clinically detectable reaction after radiothera py were screened for mutations in the ATM gene. One out of 41 cases sh owing adverse reactions was heterozygous for a mutation (insertion A a t NT 898) that is predicted to generate a truncated protein of 251 ami no acids. No truncating mutations were detected in the control subject s. On the basis of this result, the estimated percentage (95% confiden ce interval) of AT heterozygous patients in radiosensitive cases was 2 .4% (0.1-12.9%) and in control subjects (0-9.0%), We conclude that ATM gene defects are not the major cause of radiotherapy complications in women with breast cancer.