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Cancer Prev Res (Phila). 2011 Jan;4(1):23-33. doi: 10.1158/1940-6207.CAPR-10-0212. Epub 2010 Oct 26.

Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer.

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1
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria 8006, Australia.

Abstract

Women carrying germline mutations in BRCA1 are at a substantially elevated risk of breast cancer and their tumors typically have distinctive morphologic features. We hypothesized that constitutional methylation of the BRCA1 promoter region could give rise to such breast cancers in women. We selected 255 women diagnosed with breast cancer before the age of 40 years for whom BRCA1 germline mutations had not been identified. Of them, 52 had five or more of nine BRCA1 mutation-associated morphologic features (group 1), 39 had four (group 2), and 164 had three or less (group 3). The prevalence of detectable BRCA1 promoter methylation in peripheral blood DNA decreased from 31% to 10% to 5% across groups 1-3, respectively (P = 0.000002), and was significantly greater than the 4% frequency in unaffected controls (P = 0.004). Peripheral blood methylation was associated with a 3.5-fold (95% CI, 1.4-10.5) increased risk of having early onset breast cancer. Methylation was consistently mosaic in the peripheral blood where the estimated allelic frequency of BRCA1 promoter methylation ranged from 0.1% to 17%. Group 1 women, but not group 3 women, with detectable methylation of peripheral blood DNA had high levels of BRCA1 promoter methylation of their tumor DNA, indicating that constitutional BRCA1 methylation strongly predisposes toward the development of BRCA1 methylated tumors that then have features resembling BRCA1 mutated tumors. Screening peripheral blood for BRCA1 promoter methylation might thus predict early-onset breast cancers. This raises the possibility of chemoprevention or other intervention to diminish the risk of developing breast cancer in these women.

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PMID:
20978112
PMCID:
PMC4030007
DOI:
10.1158/1940-6207.CAPR-10-0212
[Indexed for MEDLINE]
Free PMC Article

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