THE ATM GENE AND SUSCEPTIBILITY TO BREAST-CANCER - ANALYSIS OF 38 BREAST-TUMORS REVEALS NO EVIDENCE FOR MUTATION

Heterozygosity for ataxia-telangiectasia (A-T), a cancer-prone recessi ve syndrome, has been associated with an increased risk of breast canc er. The gene for A-T (ATM) is located at chromosomal region 11a22-q23, a region of frequent loss of constitutional heterozygosity in breast and other tumors. Loss of constitutional heterozygosity at 11q22-q23 w as found in 47% of informative cases in the series of primary tumours analyzed in this study. To investigate the role of ATM in breast cance r, we have determined the complete genomic organization of the gene, d eveloped an exon-scanning PCR single-strand conformation polymorphism (PCR-SSCP) assay for mutation detection of ATM, and screened 38 consec utive breast tumors for mutations using both genomic DNA- and cDNA-bas ed assays. In addition to common ATM polymorphisms detected both in th e coding sequence and in flanking introns, seven unique SSCP alleles w ere identified in six tumours 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 an alysis 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 no ne of the ATM alleles found in breast cancer patients, there was no ev idence for an increased number of A-T carriers. In addition, because n o somatic mutations were found, our study rules out the ATM gene as th e frequently altered tumor suppressor gene at 11q23.