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The ATM Gene and Susceptibility to Breast Cancer: Analysis of 38 Breast Tumors Reveals No Evidence for Mutation¹

Igor Voechovsk², Debora Rasio, Liping Luo, Carmen Monaco, Lennart Hammarström, A. David B. Webster, Jan Zaloudik, Giuseppe Barbanti-Brodano, Michael James, Giandomenico Russo, Carlo M. Croce and Massimo Negrini

Karolinska Institute, Department of Bioscience at NOVUM, Center for Biotechnology, S-14157 Huddinge, Sweden [I. V., L. L., L. H., J. Z.]; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [D. R., C. M., C. M. C., M. N.]; Royal Free Hospital School of Medicine, University of London, London NW3 2PF, United Kingdom [I. V., A. D. B. W.]; Masaryk Memorial Cancer Institute, CZ-56501 Brno, Czech Republic [J. Z.]; Institute of Microbiology, University of Ferrara, I-44100 Ferrara, Italy [M. N., G. B-B.]; The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom [M. J.]; and Raggio Italgene, Laboratory of Molecular Genetics, I-00040 Pomezia, Italy [G. R.]

Heterozygosity for ataxia-telangiectasia (A-T), a cancer-prone recessive syndrome, has been associated with an increased risk of breast cancer. The gene for A-T (ATM) is located at chromosomal region 11q22–q23, a region of frequent loss of constitutional heterozygosity in breast and other tumors. Loss of constitutional heterozygosity at 11q22–q23 was found in 47% of informative cases in the series of primary tumors analyzed in this study. To investigate the role of ATM in breast cancer, we have determined the complete genomic organization of the gene, developed an exon-scanning PCR single-strand conformation polymorphism (PCR-SSCP) assay for mutation detection of ATM, and screened 38 consecutive breast tumors for mutations using both genomic DNA- and cDNA-based assays. In addition to common ATM polymorphisms detected both in the coding sequence and in flanking introns, seven unique SSCP alleles were identified in six tumor DNAs. Sequence analysis of these alleles revealed five nucleotide substitutions that were predicted to change the encoded amino acid. However, PCR-SSCP and nucleotide sequencing analysis of the paired blood samples and of an extended sample size of a total of 224 chromosomes indicated that these SSCP patterns represent constitutional rare polymorphisms with a frequency between 0.005 and 0.023. Because the majority of A-T mutations are null mutations and none of the ATM alleles found in breast cancer samples would lead to the truncation of the translation product, we conclude that, in this initial sample of sporadic breast cancer patients, there was no evidence for an increased number of A-T carriers. In addition, because no somatic mutations were found, our study rules out the ATM gene as the frequently altered tumor suppressor gene at 11q23.

¹ This work was supported by the European Commission Program BIOMED PL950914. National Cancer Institute Grant CA56366, the Karolinska Institute, IGA MZ CR 1812–3, the Associazione Italiana per la Ricerca sul Cancro, Telethon Grant E337, and the British and Swedish Medical Research Councils.

² To whom requests for reprints should be addressed, at the Karolinska Institute.

Received 3/28/96. Accepted 4/30/96.

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