Multiple genetic lesions in acquired immunodeficiency syndrome-related non-Hodgkin‧s lymphoma

Abstract

Non-Hodgkin's lymphoma (NHL) develops in about 5% to 10% of acquired immunodeficiency syndrome (AIDS) patients. The vast majority of AIDS- NHL are clinically aggressive B-cell NHL that are histologically classified as small noncleaved cell lymphoma (SNCCL), large cell immunoblastic plasmacytoid lymphoma (LC-IBPL), and large noncleaved cell lymphoma (LNCCL). In an attempt to understand the molecular pathogenesis of these tumors, we have investigated the involvement of dominantly acting oncogenes (c-myc, N-, K-, H-Ras), tumor suppressor genes (p53, RB1), and Epstein-Barr virus (EBV) infection in 27 AIDS-NHL samples (16 SNCCL, 5 LC-IBP, and 6 LNCCL). The following lesions were detected in AIDS-NHL: EBV infection (10/24; 41.6%), c-myc rearrangement (19/24; 79.1%), Ras mutation (4/27; 14.8%), and p53 loss/mutation (10/27; 37.0%). These lesions are not uniformly distributed, but, rather, cluster with specific types of AIDS-NHL: EBV infection is preferentially associated with LC-IBPL (4/4; 100%), while it is present in only a fraction of SNCCL (5/16; 31.2%) and LNCCL (1/4; 25%); c-myc oncogene activation clusters with SNCCL (16/16; 100%), whereas it is less frequent in LC-IBPL (1/4; 25%) and LNCCL (2/4; 50%); p53 inactivation is restricted to SNCCL (10/16; 62.5%) and consistently associated with c-myc activation. These data show that AIDS-NHL are associated with multiple genetic lesions that involve both proto- oncogenes and tumor suppressor genes and may accumulate in the relatively short period of time (4 to 6 years) between human immunodeficiency virus infection and AIDS-NHL development. These genetic lesions differ in the various AIDS-NHL subtypes, suggesting the involvement of distinct molecular pathway.

The Aetiology of Mixed Cryoglobulinaemia Associated with Hepatitis C Virus Infection

“…Hence, it can be postulated that HCV is the stimulus for not only the apparently benign lymphoproliferative process in essential Type II mixed cryoglobulinaemia, but also for progression to frank malignancy in a minority of patients. This formulation is consistent with the concept that has been evolving that the transformation to malignancy involves the accumulation of multiple mutations of proto-oncogenes and tumour suppression genes that may be facilitated in a setting of chronic antigenic stimulation [29][30][31].…”

High incidence of MYC rearrangement in human immunodeficiency virus‐positive plasmablastic lymphoma

“…This is consistent with the previous finding that MYC oncogene activation is detected in the majority (19/24, 79%) of patients with AIDS-associated non-Hodgkin lymphoma. 25 The present study extends a previous observation that MYC rearrangements are the main cytogenetic alterations in PBL, 9 particularly in HIV-positive cases. On the basis of these results, we deduce that MYC rearrangement may play an important role in the pathogenesis of HIV-positive PBL.…”

Kaposi's sarcoma‐associated herpesvirus DNA sequences in AIDS‐related and AIDS‐unrelated lymphomatous effusions

“…A two-step strategy was devised for the mutational analysis of p53 (exons 5-8), N-RAS (exons 1 and 2), K-RAS (exons 1 and 2). As a first phase, genomic DNAs of all samples were tested by the PCR-single-strand conformation polymorphism (PCR-SSCP) analysis with specific primers as previously reported (Ballerini et al, 1993). For each PCR fragment analysed by SSCP, at least three samples known to carry a mutation within the fragment tested were included as positive controls (Gaidano et al, 1991;Ballerini et al, 1993).…”

“…As a first phase, genomic DNAs of all samples were tested by the PCR-single-strand conformation polymorphism (PCR-SSCP) analysis with specific primers as previously reported (Ballerini et al, 1993). For each PCR fragment analysed by SSCP, at least three samples known to carry a mutation within the fragment tested were included as positive controls (Gaidano et al, 1991;Ballerini et al, 1993). Cases showing an abnormal electrophoretic migration pattern in the PCR-SSCP assay were further investigated by DNA-direct sequencing of the PCR product in order to confirm and characterize the mutation.…”