DIFFUSE LARGE-CELL LYMPHOMAS ARE DERIVED FROM MATURE B-CELLS CARRYINGV-REGION GENES WITH A HIGH-LOAD OF SOMATIC MUTATION AND EVIDENCE OF SELECTION FOR ANTIBODY EXPRESSION

In the Revised European American Lymphoma (REAL) classification, sever al subtypes of high-grade lymphomas were combined in the entity diffus e large cell lymphoma (DLL). In the present study, a total of 19 cases of DLL (10 cases of centroblastic lymphoma, 5 cases of mediastinal B cell lymphoma, 2 cases of immunoblastic lymphoma, 1 case of T cell-ric h B lymphoma and one case of large cell anaplastic lymphoma) were anal yzed for somatically mutated immunoglobulin V region genes. Somatic mu tations are acquired in the course of the germinal center (GC) reactio n and are thus found in GC B cells and their descendants, i.e. memory B cells. The V gene sequences revealed that the tumor cells of all fiv e subtypes of DLL harbored mutated V region genes and are thus derived from antigen-experienced (post) GC B cells. This indicates that from the point of view of the stage of development of the tumor precursor, the combination of those five subtypes to one entity, i.e. DLL, seems reasonable. In some cases, an unusually high frequency of somatic muta tions was detected. This may indicate that DLL are derived from GC B c ells, which, due to transforming events, stayed in the GC for prolonge d periods of time, thereby accumulating a high load of somatic mutatio n. An analysis of the mutation pattern suggests that the tumor clone o r its precursor were selected for antibody expression while acquiring somatic mutations. The latter observation discriminates DLL from class ical Hodgkin's disease, where we recently also observed a high load of somatic mutation within rearranged V region genes, but a frequent occ urrence of crippling mutations.