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ATM Mutations in Cancer Families¹

Igor Voechovsk², Liping Luo, Annika Lindblom, Massimo Negrini, A. David B. Webster, Carlo M. Croce and Lennart Hammarström

Karolinska Institute, Department of Bioscience at NOVUM, Center for BioTechnology, S-14157 Huddinge, Sweden [I. V., L. L., L. H.]; Royal Free Hospital School of Medicine, University of London, London NW3 2PF, United Kingdom [I. V., A. D. B. W.]; Department of Molecular Medicine, Karolinska Hospital, S-17176 Stockholm, Sweden [A. L.]; and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [M. N., C. M. C.]

Ataxia-telangiectasia (A-T) is a multisystem recessive disease characterized clinically by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, sensitivity to radiomimetic agents, and cancer predisposition. This pleiotropic disorder is caused by mutations in the ATM (mutated in A-T) gene, which is located in the human chromosomal region 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 response to DNA damage. Heterozygosity for A-T was previously suggested to be associated with an increased risk of tumors, particularly female breast cancer. Because a loss of constitutional heterozygosity at 11q22–q23 is a frequent event in breast and other tumors, suggesting the presence of a tumor suppressor gene(s) in this region, we screened blood DNA samples from 88 unrelated breast cancer patients of Swedish cancer families for ATM mutations using single-strand conformation polymorphism 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 breast cancer patients. Two mutations were previously found in A-T homozygotes and one mutation was a 1-bp insertion. All mutations were found in families with a large number of tumors, however, they did not cosegregate with malignancies. Although the proportion of A-T carriers in this 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.

¹ Supported by the European Commission Program BIOMED PL950914, National Cancer Institute Grant CA56366, the Karolinska Institute, the Swedish Cancer Society, and the British and Swedish Medical Research Council.

² To whom requests for reprints should be addressed, at the Karolinska Institute, Department of Bioscience at NOVUM, CBT, S-14157 Huddinge. Sweden. Phone: 46-8-6089269; Fax: 46-8-7745538; E-mail: igor.vorechovsky@cbt.ki.se.

Received 7/12/96. Accepted 8/ 8/96.

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