Serum BCL2/IGH DNA in Follicular Lymphoma Patients: A Minimal Residual Disease Marker

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Abstract
The majority of follicular lymphoma patients carry a t(14,18) juxtaposing the BCL2 oncogene to the immunoglobulin heavy chain joining region (IgH). Molecular analysis for follicular lymphoma-specific DNA translocations may permit evaluation of minimal residual disease (MRD). We identify extracellular BCL2/IGH transgene DNA in the serum of patients with follicular lymphoma, and evaluate its utility as a surrogate marker. DNA was harvested from both the sera and bone marrow of 5 stage IV follicular lymphoma patients prior to and after chemotherapy and following a novel vaccine-based regimen. Serial PCR amplifications were performed using heminested BCL2-specific major breakpoint cluster region (MBR) primers and the immunoglobulin heavy chain consensus primer. Amplification products were detected by agarose gel electrophoresis, and comparison was made to amplification products from the original tumor biopsy. Results show that four of the five lymphoma patients carried extracellular BCL2/IGH transgene DNA in their serum. The remaining patient did not have an amplification product from either the tumor or the serum, suggesting either the absence of a translocation or the presence of a variant translocation not detectable with this primer set. Transgene DNA was detectable in serum even in patients with MRD, comparing favorably with bone marrow results. In at least one patient, the presence of the transgene in serum at the conclusion of therapy preceded relapse. In conclusion, it seems that tumor-specific, extracellular DNA is present in the serum of follicular lymphoma patients, including those with MRD. Because extracellular DNA may be released into the bloodstream by tumor throughout the body it may be less subject to sampling error, and appears to be an ideal surrogate marker.

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