ATM MUTATIONS IN CANCER FAMILIES

Ataxia-telangiectasia (A-T) is a multisystem recessive disease charact erized clinically by cerebellar ataxia, oculocutaneous telangiectasias , immunodeficiency, sensitivity to radiomimetic agents, and cancer pre disposition, This pleiotropic disorder is caused by mutations in the A TM (mutated in A-T) gene, which is located in the human chromosomal re gion 11q22-q23. The ATM gene product is a member of a novel family of large proteins implicated in the regulation of the cell cycle and resp onse to DNA damage, Heterozygosity for A-T was previously suggested to he associated with an increased risk of tumors, particularly female b reast cancer, Because a loss of constitutional heterozygosity at 11q22 -q23 is a frequent event in breast and other tumors, suggesting the pr esence of a tumor suppressor gene(s) in this region, we screened blood DNA samples from 88 unrelated breast cancer patients of Swedish cance r families for ATM mutations using single-strand conformation polymorp hism analysis. All patients had a family history of tumors previously associated with A-T heterozygosity or homozygosity, We demonstrate the first three germ-line mutations in ATM identified by screening of bre ast cancer patients, Two mutations were previously found in A-T homozy gotes and one mutation was a 1-bp insertion. All mutations were found in families with a large number of tumors, however, they did not coseg regate with malignancies, Although the proportion of A-T carriers in t his sample seems to be higher than expected by chance, larger studies and pooled data sets will be required to establish that an A-T allele confers cancer susceptibility in heterozygotes.