title: Dominant negative ATM mutations in breast cancer families.
abstract: BACKGROUND
  The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families.
  
  
  METHODS
  Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided.
  
  
  RESULTS
  In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative.
  
  
  CONCLUSIONS
  At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, Australia. georgiaT@qimr.edu.au
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Magtouf
authors.initials: M
authors.lastname: Gatei
authors.forename: Helena
authors.initials: H
authors.lastname: Kelly
authors.forename: Anna
authors.initials: A
authors.lastname: Marsh
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.forename: Karen
authors.initials: K
authors.lastname: Donn
authors.forename: Margaret
authors.initials: M
authors.lastname: Cummings
authors.forename: Dale
authors.initials: D
authors.lastname: Nyholt
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Clare
authors.initials: C
authors.lastname: Scott
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Regina
authors.initials: R
authors.lastname: Bendix
authors.forename: Judy
authors.initials: J
authors.lastname: Kirk
authors.forename: Katherine
authors.initials: K
authors.lastname: Tucker
authors.forename: Margaret R E
authors.initials: MR
authors.lastname: McCredie
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Joseph
authors.initials: J
authors.lastname: Sambrook
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Mann
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases