T(14;18) translocation in chronic hepatitis C virus infection

Abstract

Pathogenic mechanisms of B-cell lymphoproliferative disorders in chronic hepatitis C virus (HCV) infection are unclear. We studied t(14;18) translocation by polymerase chain reaction in peripheral blood mononuclear cells from 50 patients with HCV-related liver disease (group A), 7 with mixed cryoglobulinemia syndrome (group B), 55 with HCV-negative liver disease (group C), and 30 with HCVnegative chronic rheumatic disorders or chronic infection by nonhepatotropic agents (group D). T(14;18) was significantly more frequent in group A (13/50 patients ‫؍‬ 26 %) and group B (5/7 ‫؍‬ 71.4%) patients than in group C (1/55 ‫؍‬ 3.6%) and group D (1/30 ‫؍‬ 3.3%) ones. Immunoblot analysis showed bcl-2 over-expression in all t(14;18)-positive samples. In group A, 10/13 (77%) patients with t(14;18) and 13/37 (35%) without t(14;18) had serum cryoglobulins in the absence of mixed cryoglobulinemia symptoms (P F .05). These data indicate that t(14;18) and bcl-2 over-expression in lymphoid cells are frequent in chronic HCV infection and suggest that this event may contribute to the pathogenesis of HCV-related lymphoproliferative disorders. (HEPATOLOGY 2000;31:474-479.)Hepatitis C virus (HCV) infection has been associated with a series of B-cell lymphoproliferative disorders (LPDs), including essential mixed cryoglobulinemia (MC), B-cell non-Hodgkin' s lymphoma (NHL), and monoclonal gammopathies. [1][2][3][4] The mechanisms involved in LPDs, either virusrelated or virus-independent, are complex and still poorly defined. MC, the LPD most strictly associated with HCV infection, is a borderline (benign/malignant) disorder in that it frequently coexists with bone-marrow aspects of NHL and evolves, in about 5% to 8% of cases, into a clinically frank B-cell malignancy. 5,6 In addition, clonal expansion of IgMproducing B cells has been detected in patients with HCVpositive MC (HCV/MC). 7 Recently, 1 patient with HCV/MC has been shown to develop a monoclonal multistep lymphoproliferative disorder associated with t(14;18) translocation in the benign phase of the disease and additional genetic alterations in the accelerated one. 8 Over-expression of bcl-2 oncoprotein has been shown by immunohistochemistry in liver lymphocyte aggregates not only in the majority of HCV-positive MC, but also in about 45% of patients with chronic HCV-related hepatitis without MC. 9 The recombination of anti-apoptotic bcl-2 proto-oncogene [t(14;18)] has been widely investigated in the field of lymphomagenetic studies. Following t(14;18), the bcl-2 locus, normally located in chromosome 18, is juxtaposed with the immunoglobulin heavy chain locus (IgH), leading to bcl-2 activation. This genetic aberration, which occurs during early B-cell development, appears to be 1 step toward the progression of a normal cell to a cancer cell 10 ; in particular, its importance in regards to cooperative activities with different oncogenes, such as c-myc, has been experimentally shown. T(14;18) characterizes most follicular B-cell lymphomas as well as some diffuse ones. Recent data...

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“…The first one is related to chronic antigenic stimulation with biological auto-immunity (RF and MC) leading to MZL [29,30], which as a result of secondary genetic events, may subsequently evolve towards transformed DLBCL. In de novo DLBCL we could hypothesise that a pro-tumour favourable environment can lead to B cell transformation [31] or that direct HCV infection of B cell may induce transformation [24].…”

Hepatitis C virus and risk of non‐Hodgkin lymphoma in British Columbia, Canada

“…26 Finally, the t(14; 18) translocation has been shown to be present in a significant percentage of peripheral blood lymphocytes in HCV infected individuals, particularly with MC. 27 This translocation is responsible for BCL-2 activation, which extends B-cell survival by inhibiting apoptosis. 28 The major strengths of this study are the large size, and the fact that the cases and controls are population based.…”

Expansion of Functionally Anergic CD21−/low Marginal Zone-like B Cell Clones in Hepatitis C Virus Infection-Related Autoimmunity

“…It also has been suggested that HCV-E2 directly activates polyclonal B cells by binding to CD81 (15). Others have proposed that direct HCV infection of B cells may cause oncogenic transformation, particularly through t(14;18) translocation (16,17).…”