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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

From the Departments of Pathology and Laboratory Medicine and Medicine, Boston University School of Medicine and Boston Medical Center; Department of Biostatistics, Boston University School of Public Health; and Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA

Address reprint requests to Carol L. Rosenberg, MD, Boston University Medical Center, 650 Albany St, EBRC-4, Boston, MA 02118; e-mail: crosenbe{at}bu.edu

PURPOSE: 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.

PATIENTS AND 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.

CONCLUSION: 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.

Supported by National Institutes of Health Public Health Service Grant No. CA81078; United States Department of Defense Breast Cancer Research Program (DAMD 17-97-7191); and Massachusetts Department of Public Health Breast Cancer Research Program.

P.S.L and B.L.S. contributed equally to this work.

Presented in part at the 96th Annual Meeting of the American Association for Cancer Research, Anaheim, CA, April 16-20, 2005.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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