IDENTIFICATION OF GENETIC LESIONS ASSOCIATED WITH DIFFUSE LARGE-CELL LYMPHOMA

Background. The pathogenesis of several subtypes of non-Hodgkin's lymp homa (NHL) is associated with specific genetic lesions involving oncog enes and tumor-suppressor genes. These lesions inlude c-myc translocat ion and p53 inactivation in small noncleaved-cell lymphoma, and bcl-2 and bcl-1 translocation in follicular (FL) and mantle-zone lymphoma, r espectively. Relatively little is known, however, about the pathogenes is of diffuse lymphoma with a large-cell component (DLLC; including la rge-, mixed-cell, and immunoblastic), the most relevant NHL type in te rms of morbidity and mortality. Since DLLC can occur 'de novo' or via histologic transformation of follicular lymphoma, it is critical to id entify lesions associated with both pathogenetic 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 seq uential biopsies were available pre- and post-transformation and (ii) identifying novel proto-oncogenes involved in DLLC pathogenesis by mol ecular analysis of chromosomal translocations affecting band 3q27, whi ch are common in DLLC. Results: Mutations of the p53 gene were detecte d 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 sho wn to be structurally altered in 33% (13/39) of DLLC samples studied, but not in other types of lymphoid malignancies. Conclusions: These re sults indicate that inactivation of the p53 tumor-suppressor gene may complement bcl-2 activation and be involved in the transformation of F L into DLLC. Activation of the bcl-6 oncogene may represent one of the steps in the pathogenesis of 'de novo' DLLC. Both lesions should prov e useful as diagnostic and prognostic markers in the clinical manageme nt of these tumors.