Methylation of BRCA1 and MGMT genes in white blood cells are transmitted from mothers to daughters

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.

Analysis of BRCA1 and RAD51C Promoter Methylation in Italian Families at High-Risk of Breast and Ovarian Cancer

“…This indicated that they occurred in a single cell relatively early during the embryonic development. This model was further supported by recent studies demonstrating that the majority of constitutional BRCA1 methylation events arose early during development and seemed to remain quite stable during life and potentially were inherited from mother to daughter [12,13]. This novel hypothesis of inheritance is controversial and needs further studies to be completely elucidated [13].…”

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

“…Although these results must be interpreted with caution as the hypermethylation levels are at the limit of detection by pyrosequencing (and thus not suitable for prediction of somatic hypermethylation), they are intriguing in the context of both possible circulating tumor DNA and findings of mosaic constitutional BRCA1 hypermethylation. Regarding the latter, mosaic constitutional BRCA1 hypermethylation has been reported in 4–7% of newborn females 40 , 41 as well as promoter methylation of BRCA1 or other cancer-related genes in peripheral blood in women who developed TNBC or high grade serous ovarian cancer 42 – 45 (see also Tang et al 46 for review). Unfortunately, a lack of corresponding fresh normal tissue hindered us from analyzing whether a mosaic methylation pattern was present also in non-malignant breast tissue.…”

Curcumin induces re‑expression of BRCA1 and suppression of γ synuclein by modulating DNA promoter methylation in breast cancer cell lines

“…Bisulfite pyrosequencing was used for DNA methylation quantification. Five different assays (35) were used to assess the methylation status of 23 CpG sites across the BRCA1 promoter. The PCR and pyrosequencing reactions were performed using PyroMark products and reagents (Qiagen, Inc.), as previously described (36).…”