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

Nodal marginal zone B-cell lymphoma (NMZL) is actually considered as a dist inct entity that must be distinguished from extra-nodal and splenic margina l zone Lymphomas. To define the cell origin and the role of antigen stimula tion we determined the nucleotide sequence of the tumor-related immunoglobu lin heavy chain variable genes in 10 cases of NMZL. The results were also e valuated on the basis of the presence of chronic hepatitis C virus (HCV) in fection. All 10 cases harbored VH somatic mutations with a sequence homolog y compared to the closest germline gene, ranging from 83.33 to 98.28%. Inte restingly, different VH segments were preferentially used in HCV-positive a nd HCV-negative patients: three of five HCV-negative NMZLs used a VH4-34 se gment joined with different D and JH segments whereas three of five HCV-pos itive NMZLs used a VH1-69 gene joined with a D3-22 and a JH4 segment, with very strong similarities in the CDR3s among the three different cases. Thes e data indicate: 1) NMZL is derived from B cells that have experienced the germinal center reaction; 2) the preferential usage of a VH1-69 segment in the majority of the HCV-positive NMZL cases with similar CDR3s suggests the presence of a common antigen, probably a HCV antigen epitope, involved in the B-cell selection; and 3) the use of a VH4-34 segment suggests a role of yet unknown B-cell superantigen(s) in the selection of tumor B-cell precur sors in HCV-negative NMZL.