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Primary lymphoma of the central nervous system (PCNSL) is a diffuse large B-cell lymphoma confined to the CNS. It has been hypothesized that antigen(s) in the CNS may trigger tumor cell proliferation. Because efforts to identify potential antigens have been unsuccessful to date, we studied the B-cell receptor in detail in a comprehensive series of 50 PCNSLs to obtain indirect information on potential antigens. Potentially functional V-D-J rearrangements were identified in all PCNSLs analyzed. Immunoglobulin heavy-chain variable gene segment (IGHV), IGHV4, was the predominant family used by 66% (33 of 50) of PCNSLs with a preferential rearrangement of the IGHV4-34 gene segment (18 [55%] of 33). The IGHV genes showed mutation frequencies from 0% to 29%, with a high average mutation frequency of 10%. In addition to 48% (24 of 50) of PCNSLs being highly mutated, 22% (11 of 50) defined a low-level mutated group. Antigen selection of the tumor cells or their precursors was indicated by replacement/silent mutation ratios and ongoing somatic hypermutation. Complementarity determining region 3 length and composition as well as the lack of stereotyped B-cell receptors suggest involvement of several antigens instead of a unique antigen recognized by the tumor cells.