title: ATM mutations in cancer families.
abstract: 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 of 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.
authors.affiliation: Karolinska Institute, Department of Bioscience NOVUM, Huddinge, Sweden. igor.vorechovsky@cbt.ki.se
authors.forename: I
authors.initials: I
authors.lastname: Vorechovský
authors.forename: L
authors.initials: L
authors.lastname: Luo
authors.forename: A
authors.initials: A
authors.lastname: Lindblom
authors.forename: M
authors.initials: M
authors.lastname: Negrini
authors.forename: A D
authors.initials: AD
authors.lastname: Webster
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.forename: L
authors.initials: L
authors.lastname: Hammarström
mesh_terms: D000225:Adenine; D000483:Alleles; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics; D018797:Cell Cycle Proteins; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D004268:DNA-Binding Proteins; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics*; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D017354:Point Mutation; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D013941:Thymine; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000225:Adenine; D013941:Thymine