title: Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer.
abstract: BACKGROUND
  Germ-line mutations in the BRCA1 and BRCA2 genes predispose women to breast cancer. BRCA1 mutations are found in approximately 12 percent of women with breast cancer of early onset, and the specific mutation causing a deletion of adenine and guanine (185delAG), which is present in 1 percent of the Ashkenazi Jewish population, contributes to 21 percent of breast cancers among young Jewish women. The contribution of BRCA2 mutations to breast cancer of early onset is unknown.
  
  
  METHODS
  Lymphocyte specimens from 73 women with breast cancer diagnosed by the age of 32 were studied for heterozygous mutations of BRCA2 by a complementary-DNA-based protein-truncation assay, followed by automated nucleotide sequencing. In addition, specimens from 39 Jewish women with breast cancer diagnosed by the age of 40 were tested for specific mutations by an allele-specific polymerase chain reaction.
  
  
  RESULTS
  Definite BRCA2 mutations were found in 2 of the 73 women with early-onset breast cancer (2.7 percent; 95 percent confidence interval, 0.4 to 9.6 percent), suggesting that BRCA2 is associated with fewer cases than BRCA1 (P=0.03). The specific BRCA2 mutation causing a deletion of thymine (6174delT), which is found in 1.3 percent of the Ashkenazi Jewish population, was observed in 1 of the 39 young Jewish women with breast cancer (2.6 percent; 95 percent confidence interval, 0.09 to 13.5 percent), indicating that it has a small role as a risk factor for early-onset breast cancer. Among young women with breast cancer, there are BRCA2 mutations that cause truncation of the extreme C terminus of the protein and that may be functionally silent, along with definite truncating mutations.
  
  
  CONCLUSIONS
  Germ-line mutations in BRCA2 contribute to fewer cases of breast cancer among young women than do mutations in BRCA1. Carriers of BRCA2 mutations may have a smaller increase in the risk of early-onset breast cancer.
authors.affiliation: Center for Cancer Risk Analysis and the Massachusetts General Hospital Cancer Center, Charlestown 02129, USA.
authors.forename: M
authors.initials: M
authors.lastname: Krainer
authors.forename: S
authors.initials: S
authors.lastname: Silva-Arrieta
authors.forename: M G
authors.initials: MG
authors.lastname: FitzGerald
authors.forename: A
authors.initials: A
authors.lastname: Shimada
authors.forename: C
authors.initials: C
authors.lastname: Ishioka
authors.forename: R
authors.initials: R
authors.lastname: Kanamaru
authors.forename: D J
authors.initials: DJ
authors.lastname: MacDonald
authors.forename: H
authors.initials: H
authors.lastname: Unsal
authors.forename: D M
authors.initials: DM
authors.lastname: Finkelstein
authors.forename: A
authors.initials: A
authors.lastname: Bowcock
authors.forename: K J
authors.initials: KJ
authors.lastname: Isselbacher
authors.forename: D A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000328:Adult; D017668:Age of Onset; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D016368:Frameshift Mutation; D019398:Genes, BRCA1; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics*; D015995:Prevalence; D012306:Risk; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors