Molecular characterization of common variable immunodeficiency-related lymphomas

Abstract

Common variable immunodeficiency (CVI) patients are at high relative risk of developing non-Hodgkin lymphomas (NHL), mainly represented by B-lineage diffuse large cell lymphomas. The molecular pathogenesis and histogenesis of CVI-related NHL are poorly understood. We have thus attempted to provide a detailed molecular characterization of their histogenesis and pathogenesis. A panel of 5 CVI-related NHL was subjected to detailed analysis of histogenetic markers (mutations of immunoglobulin variable heavy chain-IgVH and of BCL-6 genes) acquired by B-cells at the time of germinal center transit. Somatic hypermutation of IgVH and BCL-6 genes occurred in 5/5 cases; in all cases, mutations were stable with no evidence of ongoing mutation processes. In 3/5 cases, the pattern of IgVH mutations was consistent with selection and stimulation of the tumor clone by antigen. To further clarify the pathogenesis, samples were tested for inactivation by promoter hypermethylation of the genes 0(6)-methylguanine-DNA-methyltransferase (MGMT) and glutathione S-transferase (GST) p1, which code for detoxifying enzymes, as well as of death-associated protein (DAP)-kinase, coding for a proapoptotic molecule. Promoter hypermethylation of MGMT, GSTp1 and DAP-kinase was detected in 2/5, 3/5 and 3/5 CVI-related NHL, respectively. Overall, these data indicate that: i) similarly to other immunodeficiency-related NHL, CVI-related NHL derive from germinal center-related B-cells, namely centrocytes or post-germinal center B-cells; ii) antigen stimulation and selection are involved in the development of at least a fraction of these cases; iii) hypermethylation of the MGMT, DAP-kinase and GSTp1 genes occurs at sustained frequencies in CVI-related NHL and may provide novel prognostic markers and therapeutic targets for the clinical management of these lymphomas.