Identification of genetic lesions associated with diffuse large-cell lymphoma

Background: The pathogenesis of several subtypes of non-Hodgkin's lymphoma (NHL) is associated with specific genetic lesions involving oncogenes and tumor-suppressor genes. These lesions inlude c-myc translocation and p53 inactivation in small noncleaved-cell lymphoma, and bcl-2 and bcl-1 translocation in follicular (FL) and mantle-zone lymphoma, respectively. Relatively little is known, however, about the pathogenesis of diffuse lymphoma with a large-cell component (DLLC; including large-, mixed-cell, and immunoblastic), the most relevant NHL type in terms of morbidity and mortality. Since DLLC can occur 'de novo' or via histologic transformation of follicular lymphoma, it is critical to identify lesions associated with both pathogenctic pathways. Design: The present work is aimed at (i) identifying the role of cytogenetic and molecular lesions involving oncogenes or tumor-suppressor genes in the transformation of FL into DLLC in a series of 5 patients for whom sequential biopsies were available pre- and post-transformation and (ii) identifying novel proto-oncogenes involved in DLLC pathogenesis by molecular analysis of chromosomal translocations affecting hand 3q27, which are common in DLLC. Results: Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL. A novel proto-oncogene, bcl-6, coding for a zinc-finger transcription factor, was cloned from 3q27 breakpoints and shown to be structurally altered in 33% (13/39) of DLLC samples studied, but not in other types of lymphoid malignancies. Conclusions: These results indicate that inactivation of the p53 tumor-suppressor gene may complement bcl-2 activation and be involved in the transformation of FL into DLLC. Activation of the bcl-6 oncogene may represent one of the steps in the pathogenesis of 'de novo' DLLC. Both lesions should prove useful as diagnostic and prognostic markers in the clinical management of these tumors.