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Frequency and Structure of t(14;18) Major Breakpoint Regions in Non-Hodgkin's Lymphomas Typed According to the Kiel Classification: Analysis by Direct DNA Sequencing¹

Departments of Hematology and Oncology [M. K., S. E., S. W., C. P., I. B., C. N., G. K.], and Institute of Pathology [M. B.], University Clinics, Göttingen; and Institute of Pathology, Klinikum Steglitz, Free University Berlin [H. H., H. S.], Berlin, Germany

We have examined 165 unselected cases of non-Hodgkin's lymphomas for rearrangements involving the t(14;18) major breakpoint region using a polymerase chain reaction (PCR) and direct sequencing of amplified major breakpoint region bcl-2/J_H junctional regions. The lymphomas, diagnosed according to the updated Kiel classification, consisted of 33 centroblastic-centrocytic, 37 centroblastic, 27 immunocytic, 10 immunoblastic, 10 centrocytic, 2 lymphoblastic, 2 Ki-1-positive anaplastic large cell, 14 peripheral T-cell, and 4 unclassified lymphomas. In addition 18 chronic lymphocytic leukemias, 2 hairy cell leukemias, and 6 plasmacytomas were studied. In 17 cases a bcl-2/J_H gene fusion sequence was amplified by PCR. A bcl-2/J_H gene fusion was detected only in three lymphoma subgroups: 13 of 33 centroblastic-centrocytic (39%), 2 of 37 centroblastic (6%), and 2 of 27 immunocytic (8%) were positive. In two cases, major breakpoint region bcl-2 rearrangements verified by genomic Southern analysis were not detected by PCR. Direct sequencing of all 17 PCR-amplified, previously uncharacterized t(14;18) junctional regions provided corroborating evidence for the specificity of the assay. The procedure gave sequencing results even from limited amounts of lymphoma cells as obtained by fine needle aspiration of lymph nodes or from clinically uninvolved sites. Clone-specific sequences were identified due to the involvement of different J_H segments, the variations among the exact J_H and bcl-2 breakpoint positions, and the extensive incorporation of junctional region (D-) N-nucleotides. These clone-specific sequences allow accurate identification of clinically occult lymphoma cells and reduce the threat of false positive results. The finding of exceptionally long intervening sequences in some of the junctions and the partial homology with published D_H segments in three cases support the view that some of the putative N-regions harbor D_H regions.

¹ Supported by Deutsche Krebshilfe. Contains parts of the MD theses of S. W., C. N., and C. P.

² To whom requests for reprints should be addressed, at Department of Hematology/Oncology, Klinikum der Universität, Robert-Koch-Strasse 40, D-3400 Göttingen, Germany.

Received 12/17/90. Accepted 4/ 1/91.

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