title: ATM-heterozygous germline mutations contribute to breast cancer-susceptibility.
abstract: Approximately 0.5%-1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived >/=5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T-->G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are "A-T disease-causing" mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Broeks
authors.forename: J H
authors.initials: JH
authors.lastname: Urbanus
authors.forename: A N
authors.initials: AN
authors.lastname: Floore
authors.forename: E C
authors.initials: EC
authors.lastname: Dahler
authors.forename: J G
authors.initials: JG
authors.lastname: Klijn
authors.forename: E J
authors.initials: EJ
authors.lastname: Rutgers
authors.forename: P
authors.initials: P
authors.lastname: Devilee
authors.forename: N S
authors.initials: NS
authors.lastname: Russell
authors.forename: F E
authors.initials: FE
authors.lastname: van Leeuwen
authors.forename: L J
authors.initials: LJ
authors.lastname: van 't Veer
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D017398:Alternative Splicing; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000453:epidemiology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; 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