Alterations in immunoglobulin genes reveal the origin and evolution of monotypic and bitypic B cell lymphomas.

During progression of B-lymphoproliferative disorders (B-LPD), increasing divergence can be detected in histology, cytogenetics, and clinical behavior. To investigate genomic tumor cell heterogeneity, 50 biopsies of 21 patients with B-LPD of different histogenetic origin were studied for changes in the immunoglobulin gene structure during follow-up study. Ig-heavy chain (IgH) gene alterations were analyzed by Southern blotting using a panel of eight endonucleases. Ig-light chain (IgL) genes and the translocation of the bc 1-2 gene involved in t(14;18) were also studied. In seven of nine follicular lymphomas, most alterations suggested mutations in the IgH genes. Conservation of most restriction sites and of the t(14; 18) breakpoint confirmed the monoclonal origin in these tumors. Also, in two of three diffuse follicle center cell lymphomas (CLL) and in each of four immunocytomas, IgH alterations were found. In contrast, clonal changes were absent in three centrocytic lymphomas and two cases of CLL. In two follicular lymphomas with bitypic IgL expression, a common origin with subsequent divergence of the two constituents, rather than true biclonality, was indicated by the Ig gene structures. No relation was found between the frequency of somatic mutations and histologic signs of progression. These data indicate that somatic hypermutation in IgH genes is related to the histogenesis of the B-LPD and reflect the physiology of their benign counterparts in normal B cell development.