Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer.
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.
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria 8006, Australia.
Ee Ming
EM
Wong
Melissa C
MC
Southey
Stephen B
SB
Fox
Melissa A
MA
Brown
James G
JG
Dowty
Mark A
MA
Jenkins
Graham G
GG
Giles
John L
JL
Hopper
Alexander
A
Dobrovic
D017668:Age of Onset; D001315:Australia / Q000453:epidemiology; D019313:BRCA1 Protein / Q000097:blood / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D016022:Case-Control Studies; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011401:Promoter Regions, Genetic
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004273:DNA, Neoplasm