Insight into Burkitt's Lymphoma from Immunoglobulin Variable Region Gene Analysis

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Abstract
Analysis of usage of VH and VL genes, and the degree and pattern of somatic mutation, has been used to investigate the cell of origin and clonal history in cases of Burkitt's lymphoma (BL). Tumor cell lines and biopsy material from patients with endemic, sporadic and AIDS-associated BL have been compared. VH genes were most commonly derived from the VH3 (52%) and VH4 (39%) families. This shows a similar gene usage of the VH3 family to that seen in the normal peripheral blood repertoire (55%), but a biased usage of the VH4 family (22% in normal). There was no restriction in VL gene usage. This overall distribution was similar in all subsets of BL. In all categories, there was significant somatic mutation in both VH and VL sequences. There was no evidence for accumulation of mutations in cell lines cultured in vitro indicating that all mutations in BL-derived cell lines have accumulated in vivo, The mean percentage level of mutation ± ± standard deviation was greater in endemic BL (VH = 7.7 ± 4.0, VL = 5.3 ± 2.2) and AIDS-associated BL (VH = 7.5 ± 3.6, VL = 3.9 ± 1.9) than in sporadic BL (VH = 4.0 ± 2.5, VL = 2.2 ± 1.2). The pattern of somatic hypermutation was similar in VH and VL sequences of the different types of BL although the light chain genes were less mutated. Mutational patterns in the VH genes did not reveal a conventional role for antigen in selection of tumor cell sequences in 23/25 VH genes analysed. In contrast, patterns in VL sequences were consistent with a role for antigen in 8/13 sBL + eBL cases and 8/17 cases overall. The presence of EBV did not seem to influence the quantity or pattern of somatic mutations. Evidence for intraclonal variation was seen in uncloned cell lines from cases of eBL and AIDS-associated BL and confirmed in biopsy material in some, but not all cases of eBL, sBL and AIDS-associated BL examined. These common features indicate that the B-cells involved in all types of BL are derived from cells that have traversed the germinal centre, and that the somatic mutation mechanism may still be operative following neoplastic transformation. Overall, in 10/30 cases, there was evidence of significant clustering of replacement amino acids, in CDRs, particularly in VL, indicating that the B-cell of origin is likely to have been selected by antigen.