V H Gene Analysis in Sporadic Burkitt's Lymphoma: Somatic Mutation and Intraclonal Diversity with Special Reference to the Tumor Cells Involving Germinal Center

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Abstract
We analyzed the immunoglobulin heavy chain variable region (V H ) gene in seven cases of sporadic Burkitt's lymphoma (sBL) to elucidate their cell of origin. In particular, we focused on the V H gene status of tumor cells involving adjacent germinal center (GC) by microdissecting histological sections. Among the seven V H genes V H 1 family was found in two, V H 3 in four, and V H 4 in one. All rearranged V H genes demonstrated somatic mutations at percentages ranging from 1.4 to 7.5% (mean, 4.2%), which is a similar level to that seen in IgM-only B cells. Three out of four V H genes with more than 2% sequence difference from their corresponding germline counterpart showed evidence of antigen selection in their framework region 3. Three cases demonstrated signs of intraclonal diversity with a mutational frequency of 0.47-0.98%, which was 13.5-28.8 times as great as the Taq infidelity in our experimental conditions. However the level of somatic mutation and the effect of antigen selection on V H gene were diverse in these three cases, and the relationship between V H gene somatic mutation status and intraclonal diversity was unclear in sBL. In the analysis of microdissected tissues, all 20 tumor clones in the adjacent GCs showed additional replacement mutations in complementarity determining region 3, suggesting a role of antigen in tumor progression. This finding resembles the phenomenon that memory B-cells reenter into GC to undergo further affinity maturation. In contrast, 7/11 V H gene sequences irrelevant to GC were identical to those of the major tumor clone. Thus our findings suggested that sBL is derived from memory B-cells rather than GC B-cells, and that antigen stimulation is involved in the clonal expansion of a proportion of sBL.

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