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As discussed above, heterozygote carriers of ATM mutations may represent a group of individuals whose risks for developing cancer differ from that of the general population. Much needs to be learned before cancer screening issues in ATM carriers can be fully resolved. However, our knowledge has progressed to the point where several issues can begin to be addressed.

A. Identification of AT Heterozygotes

Cloning the ATM gene has opened up the possibility of developing molecular screening tests for ATM heterozygotes. Although molecular analyses can identify heterozygotes within AT families, the large size of the ATM cDNA and the existence of more than 300 "private" mutations scattered throughout the gene make it difficult to develop a practical screening test for identifying ATM heterozygotes in the general population. At the same time, functional assays are not yet specific enough to be of use in population-based screening (reviewed in Ref. 3).

B. Mammography

ATM heterozygotes would appear to be a high-risk group that could benefit from mammographic screening. However, it has been suggested that physicians consider alternatives to mammography in ATM heterozygotes (214,279). This issue has provoked much discussion, both pro and con (e.g., see Refs. 280-284). Typical radiation exposures to the breasts from mammography average 2-3 mGy

(280,285) compared to the 1-2 mGy/yr exposure from background radiation sources (286). Based on these figures, it has been estimated that the additional lifetime risk for breast cancer resulting from annual mammography is about 1.5% for the general population. The sensitivity of cells from ATM heterozygotes to radiation-induced genetic alterations averages about 25-60% higher than that of controls (e.g., see Ref. 287). This suggests that the lifetime risk of breast cancer in ATM heterozygotes from mammography is less than twofold higher than controls; perhaps 2-3% (288). This 2-3% risk compares to an estimated lifetime risk of developing breast cancer in ATM heterozygotes of >30% (224). Given that annual mammography reduces the mortality of breast cancer through early detection by ~30% or more (289), the benefits of mammographic screening would appear to outweigh the risk of mammography-induced cancer in ATM heterozygotes by age 50 years if not earlier.

C. Cancer Therapy

AT patients respond poorly to treatment regimens that include ionizing radiation, radiomimetic drugs, and topoisomerase inhibitors. Care must be taken to modify standard protocols so as to minimize iatrogenic damage, but reduced therapeutic regimens can be tolerated for these individuals (e.g., see Refs. 15, 36, and 290). ATM heterozygotes could, in theory, represent a significant fraction of cancer patients who have adverse responses to radiation and chemotherapy. Experimental evidence for this possibility is mixed (reviewed in Ref. 3). Many studies have demonstrated a group correlation between in vitro radiosensitivity and adverse reactions to radiotherapy (287,291-294). However, several small PTT-based surveys of breast cancer patients with adverse reactions to radiotherapy have failed to detect high frequencies of ATM mutations (295-297).

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