Effect of WBC BRCA1 promoter methylation on ovarian cancer risk.

Abstract

5029 Background: Recently, some studies have reported BRCA1 WBC hypermethylation to be associated with increased risk of breast cancer. We assessed WBC BRCA1 promoter methylations in ovarian (OC) and breast cancer (BC) patients and healthy controls. In an OC subgroup harboring WBC BRCA1 methylation, we confirmed promoter methylation status in normal tissue. Methods: WBC DNA from 899 OC patients, 425 BC patients and 719 healthy controls were analyzed for BRCA1 promoter methylation by methylation specific PCR. In addition, we analyzed WBC DNA from 256 OC and 393 BC patients in blood samples drawn prior to diagnosis in a population-based study. We also analyzed 24 BC patients with a family history (BRCAPRO scores > 80%; Manchester score >40) without BRCA1/2 mutations. Paraffin-embedded normal tissue from 5 OC patients harboring WBC BRCA1 methylation was analyzed for BRCA1 methylation status. Finally, to determine potential risk factors in cis, we investigated BRCA1 haplotype status in a sub-cohort of 10 individuals with WBC methylated BRCA1and 13 controls. Results: We detected WBC BRCA1 promoter hypermethylation in 2.4% of healthy controls and 3.1% of BC patients (all BC individuals). No difference in BRCA1 methylation incidence was recorded between BC patients with blood samples drawn before (4.1%) or after (2.1%) diagnosis. In contrast, we detected WBC BRCA1 methylation in 10.3% of OC patients having blood samples drawn at diagnosis. Among OC patients with blood sampling 0-13 years (median 4.6 y) prior to diagnosis, BRCA1 promoter methylation was detected in 6.6%. BRCA1 promoter methylation was associated with a non-significant elevated risk of BC (HR 1.302; 95% CI 0.697-2.431) but a significantly increased risk of OC in the cohort of patients with blood samples drawn at time of (OR 4.765; CI 2.814-8.069) or prior to (OR 2.937; CI 1.476-5.845) diagnosis. We confirmed BRCA1 promoter methylation in normal tissue from all 5 individuals analyzed, excluding WBC promoter methylation being due to circulating DNA contamination. No association between BRCA1methylation and promoter haplotype was found. Conclusions: WBC BRCA1 promoter methylation is associated with increased risk of ovarian cancer.This finding has clinical as well as biological implications..