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.

Genetic heterogeneity of AIDS‐related small non‐cleaved cell lymphoma

“…t(2;8) and t(8;22)] translocations associated with both the sporadic and the endemic type of BL (Dalla-Favera, 1993). Previous studies have shown that this combined strategy yields a positive result (by Southern blot, mutational analysis or both) in virtually all cases of BL of the immunocompetent host as well as AIDS-BL (Ballerini et al, 1993;Bhatia et al, 1994;Gaidano et al, 1997b).…”

“…All the oligonucleotides used in this study were synthesized by the solid-phase triester method. PCR-SSCP analysis was performed as previously reported (Gaidano et al, 1991;Ballerini et al, 1993;Gaidano et al, 1997b). For cases scored positive by PCR-SSCP, the presence of mutations within coding regions of the tested loci was confirmed by DNA sequencing analysis (Ballerini et al, 1993).…”

“…Analysis of c-MYC genetic lesions. Genetic lesions of c-MYC were investigated by a previously reported strategy, which included Southern blot analysis using a c-MYC third exon probe (clone MC413RC; Dalla-Favera et al, 1982) on HindIII and EcoRI digests, as well as mutational analysis of two PCR-SSCP fragments (termed F and G) spanning the c-MYC first exon-first intron border (Ballerini et al, 1993;Gaidano et al, 1997b). This combined strategy allows the molecular detection of c-MYC lesions characteristic of all types of c-MYC translocations, including classic [i.e.…”

“…Other molecular alterations tested in the AIDS-NHL panel included rearrangements of BCL-2, deletions of 6q and mutations of p53. Rearrangements of BCL-2 have been detected in a fraction of BLL of the immunocompetent host (Yano et al, 1992), whereas mutations of p53 and deletions of 6q have been reported to selectively cluster with AIDS-BL and AIDS-DLCL, respectively (Ballerini et al, 1993;Pastore et al, 1996). The genomic organization of the BCL-2 major breakpoint region (MBR) and minor cluster region (mcr) was tested as previously reported .…”

“…Conversely, AIDS-related BLL (AIDS-BLL), which includes cases morphologically 'intermediate' between typical BL and DLCL with immunoblastic features (Delecluse et al, 1993;Carbone et al, 1995), is characterized by cellular heterogeneity, marked variations of the nucleus, and a certain degree of plasmacell differentiation . Although several molecular features distinguish AIDS-BL from AIDS-DLCL (Ballerini et al, 1993;, AIDS-BLL has not been investigated in detail from a genetic viewpoint. To elucidate these issues further, we have performed a comparative genotypic analysis of BL, BLL and DLCL associated with AIDS.…”