title: Allele imbalance, or loss of heterozygosity, in normal breast epithelium of sporadic breast cancer cases and BRCA1 gene mutation carriers is increased compared with reduction mammoplasty tissues.
abstract: OBJECTIVE
  Normal-appearing breast epithelium can contain genetic abnormalities, including allele imbalance (AI), also referred to as loss of heterozygosity. Whether abnormalities are associated with cancer or cancer risk is unknown.
  
  
  METHODS
  We performed a miniallelotype, using 20 microsatellites, on each of 460 histologically normal, microdissected breast terminal ducto-lobular units (TDLUs) from three groups of women: sporadic breast cancer patients (SP; n = 18), BRCA1 gene mutation carriers (BRCA1; n = 16), and controls undergoing reduction mammoplasty (RM; n = 18). We analyzed the results using Fisher's exact tests, logistic regression, and generalized estimating equations.
  
  
  RESULTS
  AI was increased three-fold in SP and BRCA1 groups compared with RM. Both the number of TDLUs with AI increased (eight [5%] of 162 in the RM group compared with 24 [15%] of 162 in the SP and 22 [16%] of 136 in the BRCA1 groups; P = .0150), and the proportion of patients with AI increased (five [28%] of 18 in the RM group compared with 15 [83%] of 18 in the SP and 13 [81%] of 16 in the BRCA1 groups; P = .0007). The adjusted odds ratios (OR) for AI in TDLU increased in SP (OR = 15.5) and BRCA1 (OR = 13.7) patients compared with RM (P = .0025). This result was particularly evident on chromosome 17q (P = .0393), where more AI was seen in BRCA1 (OR = 12.4) than in SP (OR = 4.9) patients or RM controls.
  
  
  CONCLUSIONS
  Increased prevalence of AI in normal-appearing epithelium is associated with breast cancer and increased breast cancer risk. The increased prevalence may reflect dysregulation, even in normal-appearing epithelium, of genomic processes contributing to cancer development. The clinical significance of genetic alterations in the subset of controls remains to be determined.
authors.affiliation: Department of Pathology and Laboratory Medicine and Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Larson
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Schlechter
authors.forename: Antonio
authors.initials: A
authors.lastname: de las Morenas
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Carol L
authors.initials: CL
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000367:Age Factors; D022981:Allelic Imbalance / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000601:surgery*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000601:surgery; D018275:Carcinoma, Lobular / Q000235:genetics / Q000601:surgery; D004848:Epithelium / Q000378:metabolism / Q000601:surgery; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D016015:Logistic Models; D019656:Loss of Heterozygosity / Q000235:genetics*; D016462:Mammaplasty; D008875:Middle Aged; D016017:Odds Ratio
chemical_list: D019313:BRCA1 Protein