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The presence of circulating total DNA and methylated genes is associated with circulating tumor cells in blood from brea

2. British Journal of Cancer (BJC) . BJC publish full research papers and short communications under five broad headings: clinical studies translational therapeutics molecular diagnostics genetics and genomics epidemiology Editor-in-Chief : Adrian Harris

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The presence of circulating total DNA and methylated genes is associated with circulating tumor cells in blood from brea

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    1. 1 The presence of circulating total DNA and methylated genes is associated with circulating tumor cells in blood from breast cancer patients

    2. 2 British Journal of Cancer (BJC) BJC publish full research papers and short communications under five broad headings: clinical studies translational therapeutics molecular diagnostics genetics and genomics epidemiology Editor-in-Chief : Adrian Harris Semi-monthly Impact factor : 4.635

    3. 3 Aims to identify tumor-specific epigenetic alterations in the cell-free DNA found in the peripheral blood of breast cancer patients to assess whether a correlation exists between total or tumour-specific methylated DNA and the detection of circulating tumor cells (CTC) in peripheral blood of patients with metastatic breast cancer

    4. 4 Materials and Methods Samples: plasma serum peripheral blood breast cancer tissues (18 cases) Patients: 20 healthy volunteers 80 patients with breast cancer Group A : 4 patients with localised breast cancer Group B : 60 patients with metastatic breast cancer receiving treatment Group C : 16 patients with untreated metastatic breast cancer

    5. 5 Methods Total DNA in plasma : real-time quantitative PCR Tumor-related methylated DNA in serum (APC?RASSF1A?ESR1 ) : methylation-specific quantitative PCR Circulating tumor cells: CellSearch System (Veridex LLC, Warren, NJ, USA)

    6. 6 Results 1. Total DNA concentrations in plasma 2. Tumor-related methylated DNA in serum 3. CTC in peripheral blood 4. Association between CTC and total plasma DNA or serum methylated DNA 5. CTC, total and/or methylated DNA with clinicopathological features

    7. 7 1.Total DNA concentrations in plasma

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    9. 9 2. Tumor-related methylated DNA in serum

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    11. 11 3.CTC in peripheral blood Positive cells were identified in the blood of 65% of breast cancer patients and 10% of controls. Numbers of CTC were significantly higher in blood samples of patients with breast cancer than in healthy controls. Numbers of CTC also tended to differ between different patients groups, although this was not statistically significant.

    12. 12 4. Association between CTC and total plasma DNA or serum methylated DNA

    13. 5. CTC, total and/or methylated DNA with clinicopathological features

    14. 14

    15. 15 Discussion No correlation between methylated DNA levels in serum and corresponding levels in the primary tumour tissue was found. This could be because of the specific physiological characteristics in the progression of each tumor, for example, angiogenic capacity. Alternatively, the time of collection, the content of DNase and the presence of normal DNA in blood may obscure minute amounts of circulating tumour-related DNA. The most interesting finding of correlating methylation data to clinicopathological variables was the strong association between methylation of RASSF1A in serum DNA and HR status. It seems that epigenetic alterations in the RASSF1A gene promoter and HR regulation in breast cancer are tightly linked.

    16. 16 The observed correlation between CTC and circulating methylated DNA in our study could be interpreted in two ways: (a) CTC are a potential source of circulating tumour- specific DNA; (b) high numbers of CTC and circulating methylated DNA are both a phenotypic feature of more aggressive tumour biology. In conclusion, this study provides evidence that the detection of large amounts of free circulating total DNA and of methylated genes are associated with CTC in peripheral blood from patients with advanced breast cancer. Furthermore, the combined assessment of all three molecular markers was predictive for tumour progression.

    17. 17 Comments Several kinds of samples (plasma, serum, peripheral blood, tissue) Three markers (circulating DNA, methylated DNA, CTC) Informatively Fewer tissue samples (only 18 cases) Not related to clinical characteristics of patients such as tumor burden, staging, pathology and not compared with CEA?CA15.3 etc. Need longer follow-up: stable disease was measured up to 8 weeks after the initiation of therapy. It is not long enough.

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