A preliminary report: Frequency of A-T heterozygotes among prostate cancerpatients with severe late responses to radiation therapy

PURPOSE To investigate whether a significant proportion of pros tate cancer patients who have late sequelae after high-dose external-beam conformal ra diation therapy are radiosensitive because they are carriers of ataxia-tela ngiectasia, that is, are heterozygous for mutations in the ATM gene. PATIENTS AND METHODS A group of prostate cancer patients were selected who experienced severe late sequelae, specifically proctitis or cystitis, after high-dose external-beam conformal radiation therapy, together with a contr ol group of patients treated in the same way but who did not have severe la te effects. Blood samples were taken from these patients, genomic DNA extra cted, and mutations sought in the A TM gene. RESULTS Of 17 late-effect patients in whom most or all of the ATM gene has been examined, significant mutations (17.6%) were identified in three. No s ignificant mutations were found in the control group. The incidence of atax ia- telangiectasia heterozygotes in the United States population is 1% to 2 %. DISCUSSION These preliminary data suggest that a disproportionate number, b ut by no means all, of prostate cancer radiotherapy patients who experience severe late effects are ataxia-telangiectasia heterozygotes. If this concl usion is confirmed, these individuals could be: identified prospectively an d, with dose de-escalation, spared a great deal of discomfort and suffering . As a corollary, if most of the small late-effects population were prospec tively identifiable, the dose to the remaining population could potentially be escalated. Present methods of identifying mutations;ions in a large gen e, such as ATM, are cumbersome and expensive, but the technology is evolvin g rapidly, so that rapid screening of the ATM gene is imminent.