Ionizing radiation, breast cancer, and ataxia-telangiectasia.

It is well established that genetic predisposition (/) and environmental exposure to ionizing radiation (2) each play an important role in the etiology of breast cancer. In this issue of the Journal, Lavin et al. (3) address the important possibility that some individuals are predisposed to breast cancer because they are more susceptible than the rest of the population to the carcinogenic effects of ionizing radiation. The reasoning in their report is based on extensive information about ataxia-telangiectasia (4-15), an autosomal recessive syndrome in which the homozygous affected individuals have both very high cancer rates and an exquisite sensitivity to ionizing radiation (5,6). In childhood and adolescence, ataxia-telangiectasia homozygotes develop new cancers, predominantly lymphoid, at a rate of one for every 100 person-years (5). Severe, often lethal, necrosis of normal tissue develops rapidly when an ataxia-telangiectasia patient with leukemia or lymphoma is treated with radiotherapy at conventional doses (6). Cells from ataxia-telangiectasia patients respond abnormally to ionizing radiation in vitro, with excess cell killing as a virtual hallmark of the disorder (7). The genetic abnormality in ataxia-telangiectasia has a direct impact on cancer in the general population; an estimated 1.4% of the population carry a single ataxia-telangiectasia gene (8). Ataxia-telangiectasia heterozygotes are predisposed to breast and other cancers {9-12). The risk of breast cancer for ataxiatelangiectasia heterozygotes appears to be at least fivefold greater than that of noncarriers (9-12). Seven percent or more of all breast cancer patients are likely to carry a single ataxia-telangiectasia gene (10). This gene appears to predispose carriers to breast cancer primarily with onset before age 65 or 70 years (9,10). Thus, the proportion of ataxia-telangiectasia heterozygotes among women with early breast cancer onset may be substantially greater than 7%. Ataxia-telangiectasia heterozygous cells as a group are killed at a higher rate than cells in the control group after exposure to ionizing radiation under selected experimental conditions (13,14). These conditions do not define a useful test to detect ataxia-telangiectasia heterozygotes in populations, since there is considerable overlap between carriers and noncarriers (13,14). Because ionizing radiation can produce an excess of breast cancers in the general population, we examined the role that ionizing radiation might play in the excess breast cancers observed in close blood relatives of ataxia-telangiectasia patients. Using a straightforward case-control analysis, we found that exposure to relatively modest radiation doses, such as a woman might receive from x-ray fluoroscopic procedures involving the chest or abdomen, led to an almost sixfold excess risk of breast cancer for ataxia-telangiectasia blood relatives (10). This striking finding will be tested by us in future studies and, no doubt, by others. Its implications for medical practice are serious. If over 1 % of the population carries a gene that makes them vulnerable to cancer induction by conventional fluoroscopic procedures, some means must be found to limit the exposure of all ataxia-telangiectasia heterozygous females to such exposures. One approach would rely on genetic screening to detect ataxiatelangiectasia heterozygotes in the population. Lavin et al. (75) previously reported that heterozygous carriers of a gene for ataxia-telangiectasia could be distinguished from those in the control group by an assay that measures, by flow cytometry, the proportion of cultured lymphoblasts in G2 arrest after exposure to ionizing radiation. In this issue of the Journal, they (3) report that 8% of 24 age-matched control women and 20% of 108 patients with diagnosed breast cancer had elevated values on this assay that were comparable to those they had observed previously in obligate ataxia-telangiectasia heterozygotes. Lavin et al. (3) also found an elevated proportion of high values in their assay in a group of women who had severe immediate reactions to radiation treatment of their breast cancers. How can these results be interpreted? These and other important questions must be answered. For example, we do not yet know that having an excessive immediate reaction to radiation therapy or having a high value in the assay of Lavin et al. (3,15) are genetic characteristics. Evidence must be sought in family studies. Only when it is clearly established that these are genetically influenced characteristics will it be possible to search for specific genes controlling them. Further, do we know that ataxia-telangiectasia heterozygotes are reliably identified by this assay? The proportion of control individuals scoring abnormally high was about 8% (3), considerably higher than even the most generous estimate of the frequency of ataxia-telangiectasia heterozygotes in the general population (8). Can this assay be replicated in other laboratories? How reliable is it as a population test for the ataxia-telangiectasia heterozygote under stringent blinded conditions? My previous experience with proposed cell biological tests for the ataxia-telangiectasia heterozygote has been discouraging, with random or almost random results when blinded samples were sent to several different laboratories that had proposed an ataxia-telangiectasia heterozygote assay (16; unpublished data).