Primary Central Nervous System Lymphomas Are Derived from Germinal-Center B Cells and Show a Preferential Usage of the V4–34 Gene Segment

Abstract

Primary central nervous system lymphomas (PCNSLs) have recently received considerable clinical attention due to their increasing incidence. To clarify the histogenetic origin of these intriguing neoplasms, PCNSLs from 10 HIV-negative patients were analyzed for immunoglobulin (Ig) gene rearrangements. All tumors exhibited clonal IgH gene rearrangements. Of the 10 cases, 5 used the V4-34 gene segment, and all of these lymphomas shared an amino acid exchange from glycine to aspartate due to a mutation in the first codon of the complementarity-determining region 1. No preferential usage of D(H), J(H), V(kappa), J(kappa), V(lambda), or J(lambda) gene segments was observed. All potentially functional rearrangements exhibited somatic mutations. The pattern of somatic mutations indicated selection of the tumor cells (or their precursors) for expression of a functional antibody. Mean mutation frequencies of 13. 2% and 8.3% were detected for the heavy and light chains, respectively, thereby exceeding other lymphoma entities. Cloning experiments of three tumors showed ongoing mutation in at least one case. These data suggest that PCNSLs are derived from highly mutated germinal-center B cells. The frequent usage of the V4-34 gene and the presence of a shared replacement mutation may indicate that the tumor precursors recognized a shared (super) antigen.

Immunoglobulin Gene Mutations and Frequent Use of VH1-69 and VH4-34 Segments in Hepatitis C Virus-Positive and Hepatitis C Virus-Negative Nodal Marginal Zone B-Cell Lymphoma

“…The VH4-34 gene is used in ϳ5% of healthy adult B lymphocytes 26 and is frequently found in diffuse large-cell lymphoma, primary central nervous system lymphoma, B-chronic lymphocytic leukemia, and autoimmune disorders, but never in multiple myeloma. [27][28][29][30][31][32] Interestingly, the VH4-34 gene is VH genes, immunoglobulin heavy chain variable gene; R, replacement mutation; S, silent mutation; CDR, complementary determining regions; FR, framework regions; Obs R/S CDR and Obs R/S FR, number of the observed R and S mutations in the CDR and FR, respectively; Exp R CDR and Exp R FR, number of expected R mutation in the CDR and FR, respectively; pCDR and pFR, probability that excess or scarcity of the R mutations in the VH gene CDR or FR resulted from chance only; ND, not determined.…”

Molecular pathology of lymphoma

“…65,66 Interestingly, a similar high mutation IgV frequency has been reported in primary CNS lymphoma. 67,68 The findings of a large somatic mutation load in the IgV genes of VRL, together with the tumour cell immunophenotype (IRF4/MUM1 þ , BCL6 þ / À , CD10 þ ), suggest that it is a DLBCL of ABC type.…”

Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma

“…3 The diagnoses were based on a combination of routine morphology and immunohistochemistry using monoclonal mouse antibodies against CD20, CD45, Ki-67 (MIB-1), IgM, IgG, BCL6, and MUM1/IRF4 as reported earlier. 13,14 The clinical characteristics are summarized in Table 1.…”