Rearranged Ig Heavy Chain DNA Is Detectable in Cell-Free Blood Samples of Patients With B-Cell Neoplasia

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Abstract
Tumor-derived DNA has been shown in various cell-free body fluids. In this study, soluble tumor-derived DNA was analyzed in serum and plasma samples of patients with B-cell malignancies. DNA was extracted from tumor cell specimens as well as serum and plasma samples collected from 110 patients with non-Hodgkin's lymphoma and acute B-precursor lymphoblastic leukemia and was subjected to polymerase chain reaction (PCR) analysis for rearranged immunoglobulin heavy chain DNA. In 54% of serum or plasma samples analyzed at different times before and during treatment, clonal DNA from a rearranged immunoglobulin heavy chain locus was detectable. When examined at diagnosis and before any treatment, clonotypic DNA was found in serum or plasma of 86% of the patients. Serum or plasma from patients with systemic or bulky disease was uniformly PCR positive, whereas clonotypic DNA was also recovered from the serum or plasma from the majority of patients with limited disease stages. Degradation of clonal DNA by nucleases in vitro was shown to be one cause of false-negative PCR results. This technical drawback can be relieved by adding a nuclease inhibitor like EDTA, ie, by using plasma instead of serum for PCR analysis. Treatment of patients with cytotoxic drugs was followed by rapid clearance of DNA from the peripheral blood, suggesting that soluble tumor-derived DNA might be associated with viable and proliferating tumor cells. Follow-up studies showed a close correlation of persisting soluble tumor-derived DNA with resistant disease or early relapse. In summary, these data suggest that tumor-derived DNA can be detected in serum or plasma of the majority of patients with B-cell malignancies and that testing of serum or plasma for tumor-associated DNA may be a novel parameter for monitoring response to treatment.