Intraclonal offspring expansion of gastric low-grade MALT-type lymphoma: evidence for the role of antigen-driven high-affinity mutation in lymphomagenesis.

Recent studies have shown that gastric mucosa-associated lymphoid tissue (MALT)-type lymphoma B cells are the malignant counterparts of hypermutated, postgerminal-center memory B cells. To further elucidate the role of antigen selection in the evolution of gastric low-grade MALT-type lymphoma, we analyzed intraclonal variations of the immunoglobulin heavy-chain variable region (Ig VH) genes expressed in three cases of lymphoma. The Ig VH genes expressed by tumor cells were amplified by PCR using primers for individual tumor-specific markers (complementarity-determining region 3 (CDR3)) and primers for six VH family leaders and then sequenced. The corresponding germ-line VH gene from these patients was also sequenced. The somatic mutations were highly concentrated in the CDR or framework region, with a clustering of replacement mutations in the CDR but only a few in the framework region. Each of the Ig VH genes of tumor cell clones of Cases 1 and 3 showed different mutations, whereas Case 2 showed no intraclonal variation. Although all three mutation pattern variants of Cases 1 and 3 occurred in postgerminal memory B cells, only one offspring from each case resulted in a dominant expansion. This finding suggests that antigen-driven high-affinity somatic mutation may play an important role in the expansion of intraclonal offspring from low-grade MALT-type lymphomas.