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Despite the increasing clinical applications of circulating EBV DNA analysis as a tumor marker, the molecular nature of these EBV DNA molecules remains unclear. We subjected plasma/serum samples of nasopharyngeal carcinoma and lymphoma patients to DNase digestion and ultracentrifugation and showed that circulating EBV DNA molecules are "naked" DNA fragments instead of being contained inside virions. We further showed that these EBV DNA fragments were relatively short, and 87% of them were shorter than 181 bp. These results provide fundamental information that may improve our understanding of the release of tumor-derived nucleic acids into the blood of cancer patients.

Purpose: Natural killer/T-cell (NK/T-cell) lymphoma is a highly aggressive tumor for which no serological tumor marker has yet been established to be useful clinically. We investigated the potential of circulating EBV DNA as a tumor marker for this malignancy., Experimental Design: A real-time quantitative PCR assay was used to measure circulating EBV DNA., Results: Plasma EBV DNA levels were measured in 18 patients with NK/T-cell lymphoma at presentation and during therapy. Plasma EBV DNA was detected in 17 of the 18 patients (median, 659 copies/ml; interquartile range, 181-17,042 copies/ml) but in none of 35 control subjects (p < 0.0001). Serial measurements of plasma EBV DNA levels during therapy showed a close correlation between clinical response and changes in plasma EBV DNA levels. Clinically responding patients showed a fall of plasma EBV DNA levels to low or undetectable levels, whereas those who failed therapy showed a rapid increase in plasma EBV DNA levels. Most importantly, patients with high baseline plasma EBV DNA levels (> or = 600 copies/ml) demonstrated a significantly inferior survival than those with low baseline plasma EBV DNA (< 600 copies/ml; 21% versus 78%; P = 0.024)., Conclusions: Plasma EBV DNA, as measured by real-time quantitative PCR, is a useful tumor marker for diagnosis, disease monitoring, and prediction of outcome in patients with NK/T-cell lymphoma.

Epstein-Barr virus (EBV) is a human lymphotrophic herpesvirus implicated in the development of several lymphoid malignancies. Recently, detection of cell-free EBV DNA in sera or plasma from patients with EBV-associated malignancies has been reported. However, most published studies are qualitative in nature, with only a few providing quantitative data. We have described the temporal changes of plasma EBV DNA levels in patients with EBV-associated lymphoid malignancies during therapy using quantitative real-time PCR. A close correlation between plasma EBV DNA levels and therapeutic response was observed. Our aim was to update our results and to assess the role of the plasma EBV DNA levels as a molecular marker for disease monitoring in patients with EBV-associated lymphoid malignancies.

Cell-free Epstein-Barr virus (EBV) DNA has recently been detected in the plasma and serum of patients with Hodgkin's disease, post-transplant lymphoproliferative disease (PTLD) and acquired immunodeficiency syndrome-related lymphoma. However, no data are available on the temporal variation of plasma/serum EBV DNA levels in patients with EBV-associated lymphoid malignancies during the course of therapy. Using a real-time quantitative polymerase chain reaction assay, we studied the plasma EBV DNA levels in 13 patients with EBV-associated lymphoid malignancies (six patients with Hodgkin's disease, four with nasal natural killer/T-cell lymphoma, two cases of PTLD and one patient with Burkitt's lymphoma) at presentation and during therapy. Plasma EBV DNA was detected in 12 of the 13 patients (median 2,266 copies/ml; interquartile range 181-8,379 copies/ml), but not in any of 35 healthy control subjects (P < 0.0001). The EBV status in tumour cells was also examined in 12 of these patients using in situ hybridization for EBV-encoded small RNAs (EBERs). EBER positivity was observed in 11 patients, all of whom had EBV DNA detectable in plasma. The one patient who had no detectable plasma EBV DNA was also negative for EBERs in tumour tissue. Serial measurements of plasma EBV DNA levels were performed in nine of the patients during the course of therapy. All patients who responded to therapy demonstrated a significant reduction of plasma EBV DNA to low or undetectable levels, whereas in two patients with ineffective therapy, disease progression was associated with a rapid increase in plasma EBV DNA levels. We concluded that plasma EBV DNA is detectable in a wide range of EBV-associated lymphoid malignancies. As plasma EBV DNA levels correlate well with the therapeutic response, such analysis may be a valuable tool for monitoring clinical progress.