Dataset Information

Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study.

ABSTRACT:

Background

Epigenetic changes are emerging as one of the most important events in carcinogenesis. Two alterations in the pattern of DNA methylation in breast cancer (BC) have been previously reported; active estrogen receptor-alpha (ER-alpha) is associated with decreased methylation of ER-alpha target (ERT) genes, and polycomb group target (PCGT) genes are more likely than other genes to have promoter DNA hypermethylation in cancer. However, whether DNA methylation in normal unrelated cells is associated with BC risk and whether these imprints can be related to factors which can be modified by the environment, is unclear.

Methodology/principal findings

Using quantitative methylation analysis in a case-control study (n = 1,083) we found that DNA methylation of peripheral blood cell DNA provides good prediction of BC risk. We also report that invasive ductal and invasive lobular BC is characterized by two different sets of genes, the latter particular by genes involved in the differentiation of the mesenchyme (PITX2, TITF1, GDNF and MYOD1). Finally we demonstrate that only ERT genes predict ER positive BC; lack of peripheral blood cell DNA methylation of ZNF217 predicted BC independent of age and family history (odds ratio 1.49; 95% confidence interval 1.12-1.97; P = 0.006) and was associated with ER-alpha bioactivity in the corresponding serum.

Conclusion/significance

This first large-scale epigenotyping study demonstrates that DNA methylation may serve as a link between the environment and the genome. Factors that can be modulated by the environment (like estrogens) leave an imprint in the DNA of cells that are unrelated to the target organ and indicate the predisposition to develop a cancer. Further research will need to demonstrate whether DNA methylation profiles will be able to serve as a new tool to predict the risk of developing chronic diseases with sufficient accuracy to guide preventive measures.

SUBMITTER: Widschwendter M

PROVIDER: S-EPMC2442168 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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Publications

Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study.

Widschwendter Martin M Apostolidou Sophia S Raum Elke E Rothenbacher Dietrich D Fiegl Heidi H Menon Usha U Stegmaier Christa C Jacobs Ian J IJ Brenner Hermann H

PloS one 20080716 7

<h4>Background</h4>Epigenetic changes are emerging as one of the most important events in carcinogenesis. Two alterations in the pattern of DNA methylation in breast cancer (BC) have been previously reported; active estrogen receptor-alpha (ER-alpha) is associated with decreased methylation of ER-alpha target (ERT) genes, and polycomb group target (PCGT) genes are more likely than other genes to have promoter DNA hypermethylation in cancer. However, whether DNA methylation in normal unrelated ce ...[more]

PMID: 18628976

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Project description:BackgroundAberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy.MethodologyThis was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day -7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate.Main findings16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1-2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively.ConclusionsHydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.

Dataset Information

Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study.

Background

Methodology/principal findings

Conclusion/significance

Publications

Epigenotyping in peripheral blood cell DNA and breast cancer risk: a proof of principle study.

Similar Datasets

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