Abstract
BackgroundConstitutive methylation of tumor suppressor genes are associated with increased cancer risk. However, to date, the question of epimutational transmission of these genes remains unresolved. Here, we studied the potential transmission of BRCA1 and MGMT promoter methylations in mother-newborn pairs.MethodsA total of 1014 female subjects (cancer-free women, n = 268; delivering women, n = 295; newborn females, n = 302; breast cancer patients, n = 67; ovarian cancer patients, n = 82) were screened for methylation status in white blood cells (WBC) using methylation-specific PCR and bisulfite pyrosequencing assays. In addition, BRCA1 gene expression levels were analyzed by quantitative real-time PCR.ResultsWe found similar methylation frequencies in newborn and adults for both BRCA1 (9.9 and 9.3%) and MGMT (12.3 and 13.1%). Of the 290 mother-newborn pairs analyzed for promoter methylation, 20 mothers were found to be positive for BRCA1 and 29 for MGMT. Four mother-newborn pairs were positive for methylated BRCA1 (20%) and nine pairs were positive for methylated MGMT (31%). Intriguingly, the delivering women had 26% lower BRCA1 and MGMT methylation frequencies than those of the cancer-free female subjects. BRCA1 was downregulated in both cancer-free woman carriers and breast cancer patients but not in newborn carriers. There was a statistically significant association between the MGMT promoter methylation and late-onset breast cancers.ConclusionsOur study demonstrates that BRCA1and MGMT epimutations are present from the early life of the carriers. We show the transmission of BRCA1 and MGMT epimutations from mother to daughter. Our data also point at the possible demethylation of BRCA1and MGMT during pregnancy.
Highlights
Constitutive methylation of tumor suppressor genes are associated with increased cancer risk
We investigated the prevalence of BRCA1 and MGMT promoter methylations in white blood cells (WBC) from cancer-free women and newborn females
Cancer-free women and newborns have similar frequencies of WBC BRCA1 promoter methylation To investigate the potential transmission of methylated BRCA1 promoter from mother to daughter, we examined the BRCA1 promoter methylation status in DNA from WBC using MSP assay in a cohort of 865 female subjects
Summary
Constitutive methylation of tumor suppressor genes are associated with increased cancer risk. Defects in epigenetic manipulation, which results in the atypical transcriptional silencing of active genes and/or reactivation of silent genes, are defined as “Epimutation” [1] This non-genetic change is a potent mechanism responsible for the suppression of various tumor suppressor genes; it is considered as a mechanism for cancer predisposition [2]. Constitutive BRCA1 methylation has been found to be associated with a 3.5-fold increase in the risk of developing early-onset breast cancer and a major predisposition factor for serous ovarian cancer [8,9,10,11,12,13]. This renders the constitutive BRCA1 promoter methylation as a potential predictive biomarker for breast and ovarian cancer predisposition [12]
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