title: Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history.
abstract: BACKGROUND
  An increased incidence of breast carcinoma has been reported among relatives of individuals who are affected with the rare recessive disorder, ataxia-telangiectasia (A-T), and who are heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. However, most studies of breast carcinoma cases from the general population have failed to find a higher incidence of ATM mutations in cases when compared with controls.
  
  
  METHODS
  Genomic DNA samples from 258 individuals were screened for mutations of all types in each of the 62 coding exons of the ATM gene; 142 of these were from breast carcinoma cases with a first-degree family history or early age at diagnosis, 35 were from cases selected for the presence of either known disease-related mutations (n = 25) or missense alterations of unknown consequences (n = 10) in BRCA1 or BRCA2, and 81 were from matched controls.
  
  
  RESULTS
  A total of 12 individuals with ATM mutations were identified, 11 among 142 breast carcinoma cases (7.7%; 95% CI, 3.9-13.4%) and 1 among 81 controls (1.2%; 95% CI, 0.0-6.7%) (P = 0.06). All mutations detected were of the missense type; none were predicted to truncate the ATM protein. Among cases, mutations were found exclusively in patients with a family history of breast carcinoma (12.1%; 95% CI, 6.2-20.6%) (P = 0.02). Similar frequencies of ATM mutations were found in 35 additional cases selected for the presence of BRCA1 or BRCA2 mutations when compared with cases overall.
  
  
  CONCLUSIONS
  ATM mutations, specifically missense mutations, are more common in breast carcinoma cases selected for first-degree family history and early age at diagnosis.
authors.affiliation: Molecular Genetics Program, Virginia Mason Research Center, 1201 Ninth Avenue, Seattle, WA 98101-2795, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Teraoka
authors.forename: K E
authors.initials: KE
authors.lastname: Malone
authors.forename: D R
authors.initials: DR
authors.lastname: Doody
authors.forename: N M
authors.initials: NM
authors.lastname: Suter
authors.forename: E A
authors.initials: EA
authors.lastname: Ostrander
authors.forename: J R
authors.initials: JR
authors.lastname: Daling
authors.forename: P
authors.initials: P
authors.lastname: Concannon
mesh_terms: D000328:Adult; D017668:Age of Onset; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics* / Q000503:physiopathology; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D009363:Neoplasm Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases