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Molecular and Clinical Features of Non-Burkitt’s, Diffuse Large-Cell Lymphoma of B-Cell Type Associated With the c-MYC/Immunoglobulin Heavy-Chain Fusion Gene

From the First Division, Department of Internal Medicine, and Laboratory of Anatomical Pathology, Faculty of Medicine, The Center for Molecular Biology and Genetics, Kyoto University, Kyoto; and First Department of Internal Medicine, Kansai Medical University, Moriguchi, Japan.

Address reprint requests to Hitoshi Ohno, MD, First Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, 54 Shogoin-Kawaramachi, Sakyo-ku, Kyoto 606-8507, Japan; email hohno{at}kuhp.kyoto-u.ac.jp

PURPOSE: t(8;14)(q24;q32) and/or c-MYC/immunoglobulin heavy-chain (IGH) fusion gene have been observed not only in Burkitt’s lymphoma (BL) but also in a proportion of non-BL, diffuse large-cell lymphoma of B-cell type (DLCL). We explored molecular features of DLCL with c-MYC/IGH fusion and the impact of this genetic abnormality on clinical outcome of DLCL.

PATIENTS AND METHODS: A total of 203 cases of non-BL DLCL were studied. Genomic DNA extracted from tumor tissues was subjected to long-distance polymerase chain reaction (LD-PCR) using oligonucleotide primers for exon 2 of c-MYC and for the four constant region genes of IGH.

RESULTS: Twelve cases (5.9%) showed positive amplification; one had a c-MYC/Cµ, nine had a c-MYC/C, and two had a c-MYC/C fusion sequence. Restriction and sequence analysis of the LD-PCR products, ranging from 2.3 to 9.4 kb in size, showed that breakage in the 12 cases occurred within a 1.5-kb region that included exon 1 of c-MYC in combination with breakpoints at the switch regions of IGH (10 of 12). In 10 cases, Myc protein encoded by the fusion genes demonstrated mutations and/or deletions. Six cases had additional molecular lesions in BCL-2 or BCL-6 and/or p53 genes. The age range of the 12 patients was 44 to 86 years, with a median age of 65.5 years. Five patients had stage I/II disease, and seven had stage III/IV disease. Lactate dehydrogenase was elevated in nine of 11 subjects. Seven showed involvement of the gastrointestinal tract. All patients were treated by surgery and/or chemoradiotherapy; six died of the disease within 1 year, resulting in the poorest 1- and 2-year survival rates among DLCL subgroups.

CONCLUSION: The c-MYC/IGH fusion gene of DLCL is identical to that of the sporadic type of BL (sBL). DLCL with c-MYC/IGH shares clinical features with sBL but is characterized further by an older age distribution.

T.A. is a fellow in cancer research of the Japan Society for the Promotion of Science, Tokyo, Japan.

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