HETEROZYGOUS ATM MUTATIONS DO NOT CONTRIBUTE TO EARLY-ONSET OF BREAST-CANCER

Ataxia telangiectasia (AT) is a recessive syndrome, including cerebell ar degeneration, immunologic defects and cancer predisposition(1,2), a ttributed to mutations in the recently isolated ATM (ataxia telangiect asia, mutated) gene(3). AT is diagnosed in 1/40,000 to 1/100,000 live births, with carriers calculated to comprise similar to 1% of the popu lation. Studies of AT families have suggested that female relatives pr esumed to be carriers have a 5 to 8-fold increased risk for developing breast cancer(4,5), raising the possibility that germline ATM mutatio ns may account for similar to 5% of all breast cancer cases. The incre ased risk for breast cancer reported for AT family members has been mo st evident among younger women, leading to an age-specific relative ri sk model predicting that 8% of breast cancer in women under age 40 ari ses in AT carriers, compared with 2% of cases between 40-59 years(6). To test this hypothesis, we undertook a germ-line mutational analysis of the ATM gene in a population of women with early onset of breast ca ncer, using a protein truncation (PTT) assay to detect chain-terminati ng mutations, which account for 90% of mutations identified in childre n with AT(7-11). We detected a heterozygous ATM mutation in 2/202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2/401 (0.5% ) women with early onset of breast cancer (P = 0.6). We conclude that heterozygous ATM mutations do not confer genetic predisposition to ear ly onset of breast cancer.