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Hypermethylation of the Breast Cancer–Associated Gene 1 Promoter Does Not Predict Cytologic Atypia or Correlate with Surrogate End Points of Breast Cancer Risk

¹ Duke University Medical Center, Durham, North Carolina; ² The Ohio State University Medical Center, Columbus, Ohio; ³ University of Kansas Medical Center, Kansas City, Kansas; and ⁴ Yale-New Haven Medical Center, New Haven, Connecticut

Requests for reprints: Victoria L. Seewaldt, Duke University Medical Center, Box 2628, Durham, NC 27710. Phone: 919-668-2455; Fax: 919-668-2458. E-mail: seewa001{at}mc.duke.edu

Mutation of the breast cancer–associated gene 1 (BRCA1) plays an important role in familial breast cancer. Although hypermethylation of the BRCA1 promoter has been observed in sporadic breast cancer, its exact role in breast cancer initiation and association with breast cancer risk is unknown. The frequency of BRCA1 promoter hypermethylation was tested in (a) 14 primary breast cancer biopsies and (b) the initial random periareolar fine-needle aspiration (RPFNA) cytologic samples obtained from 61 asymptomatic women who were at increased risk for breast cancer. BRCA1 promoter hypermethylation was assessed from nucleotide –150 to nucleotide +32 relative to the transcription start site. RPFNA specimens were stratified for cytologic atypia using the Masood cytology index. BRCA1 promoter hypermethylation was observed at similar frequency in nonproliferative (normal; Masood 10: 18%, 2 of 11), hyperplastic (Masood 11-13: 15%, 6 of 41), and atypical cytology (Masood 14-17: 22%, 4 of 18; P = 0.79). BRCA1 promoter hypermethylation was not associated with (a) family history of breast or ovarian cancer or (b) calculated Gail or BRCAPRO risk score. BRCA1 promoter hypermethylation was associated with (a) age (P = 0.028) and (b) the combined frequency of promoter hypermethylation of the retinoic acid receptor-ß2 (RARB) gene, estrogen receptor- (ESR1) gene, and p16 (INK4A) gene (P = 0.003). These observations show that BRCA1 promoter hypermethylation (a) is not associated with breast cancer risk as measured by mathematical risk models and (b) does not predict mammary atypia in RPFNA cytologic samples obtained from high-risk women. (Cancer Epidemiol Biomarkers Prev 2007;16(1):50–6)

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