Identification of germline missense mutations and rare allelic variants inthe ATM gene in early-onset breast cancer

Epidemiological studies have shown an increased risk of breast cancer in ob ligate ataxia telangiectasia (A-T) heterozygotes. We analyzed 100 samples f rom young breast cancer patients for mutations in ataxia-telangiectasia mut ated (ATM), the gene responsible for the autosomal recessive condition, A-T , to determine whether A-T heterozygosity predisposes such individuals to d evelop breast cancer. These patients were selected from families with a mod erate or absent family history of breast cancer and included a subset of 16 radiosensitive patients. Forty-four germline sequence variants were detect ed by fluorescent chemical cleavage of mismatch of RT-PCR products. These i ncluded seven rare variants found in nine patients (three described for the first time), but no truncating mutations. Although three variants were det ected in the radiosensitive subset, this was not statistically significant compared to the nonradiosensitive group. One variant, G2765S, is likely to be a missense mutation, but the other six variants probably represent rare polymorphisms. However, five of the seven rare germline variants detected s howed loss of heterozygosity of the wild-type ATM allele for one or more ma rkers close to the ATM locus in marched tumor DNA. This high rate of somati c inactivation of ATM may indicate either that these rare variants play a r ole in breast cancer development or alternatively that a neighboring tumor suppressor gene is important for tumorigenesis. We found germline truncatin g ATM mutations to be rare in these young breast cancer patients and theref ore they are unlikely to play a role in the etiology of their disease. (C) 1999 Wiley-Liss, Inc.