IMMUNOGLOBULIN V-H GENES OF HIGH-GRADE MUCOSA-ASSOCIATED LYMPHOID-TISSUE LYMPHOMAS SHOW A HIGH-LOAD OF SOMATIC MUTATIONS AND EVIDENCE OF ANTIGEN-DEPENDENT AFFINITY MATURATION

High-grade mucosa-associated lymphoid tissue (MALT) B-cell lymphoma of the stomach shares several features with its low-grade counterpart. T he latter is nearly invariably associated with Helicobacter pylori, an d the tumor cells of all MALT lymphomas normally express surface antig en receptors; thus, it is possible that the high-grade type, like the low-grade type, is still influenced by interaction with antigen. In th e present study, we analyzed the immunoglobulin heavy chain variable ( V)-region genes from eight cases of high-grade MALT lymphoma and one c ase of Burkitt's lymphoma of the stomach. The V-region genes revealed somatic mutations in all cases, leading to the conclusion that high-gr ade MALT lymphomas derive from antigen-experienced (post-) germinal ce nter B-cells. Nonrandom distribution of replacement and silent mutatio ns within the gene segments in seven of the eight MALT lymphomas indic ated that these V-region genes were selected by antigen, at least for some period of time. Five of the cases showed an unusual mutation patt ern that was suggestive of selection by autoantigen or superantigen ra ther than heterogenous antigen. Analysis for intraclonal variations re vealed evidence of ongoing mutations in two cases. In these cases, the tumor clones probably derived from cells affected by a germinal cente r B-cell reaction, as the microenvironment of the germinal center is r equired for maintenance of an active hypermutation mechanism. On the o ther hand, in another two cases, no evidence of intraclonal variations was found. Thus, either these tumor clones were derived from postgerm inal center B-cells, or the hypermutation mechanism in the germinal ce nter ceased after some period of time. Given the mutation pattern, it is possible that high-grade MALT lymphomas emerge from further transfo rmation of low-grade MALT lymphomas with accumulation of additional mu tations in the complementarity-determining regions.