Molecular signature in HCV-positive lymphomas.

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2012, Article ID 623465, 9 pages doi:10.1155/2012/623465 Review Article Molecular Signature in HCV-Positive Lymphomas Valli De Re,1 Laura Caggiari,1, 2 Marica Garziera,1 Mariangela De Zorzi,1 and Ombretta Repetto1 1 Unit of Clinical and Experimental Pharmacology, IRCCS, Centro di Riferimento Oncologico, National Cancer Institute, 33081 Aviano, Pordenone, Italy 2 Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico, IRCCS, 33081 Aviano, Pordenone, Italy Correspondence should be addressed to Valli De Re, Received 24 April 2012; Revised 29 June 2012; Accepted 3 July 2012 Academic Editor: Domenico Sansonno Copyright © 2012 Valli De Re et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hepatitis C virus (HCV) is a positive, single-stranded RNA virus, which has been associated to different subtypes of B-cell nonHodgkin lymphoma (B-NHL). Cumulative evidence suggests an HCV-related antigen driven process in the B-NHL development. The underlying molecular signature associated to HCV-related B-NHL has to date remained obscure. In this review, we discuss the recent developments in this field with a special mention to different sets of genes whose expression is associated with BCR coupled to Blys signaling which in turn was found to be linked to B-cell maturation stages and NF-κb transcription factor. Even if recent progress on HCV-B-NHL signature has been made, the precise relationship between HCV and lymphoma development and phenotype signature remain to be clarified. 1. Introduction In the early 2000s, a large body of experimental and epidemiological evidence established an association between B-cell non-Hodgkin lymphoma (B-NHL) and hepatitis C virus (HCV). Epidemiological studies demonstrated that HCV-related type-II mixed cryoglobulinemia herein named (MC), a B-cell lymphoproliferative autoimmune disease, favor lymphoma progression [1]. Approximately 1 of 20 instances out of B-NHLs in Italy may be attributable to HCV [2, 3]. HCV incidence was found to be higher in the south and on the islands [3]. The burden of clinically relevant HCV-positive cases in Italy is on the decline [4]. As of today, the precise mechanism of lymphoma onset remains unclear. HCV has been demonstrated to infect Bcells but the level of replication is low and is only demonstrated in a few cases. The mechanism of B-cell tropism remains elusive, and cell cultures producing HCV are limited [5–7]. Alternatively, though not necessarily in opposition, cumulative evidence supports a role of HCV as an etiological agent for indirect stimulation of specific B-cells, resulting in progressive clonal expansion of B-cells [8–10]. The incidence of cryoglobulinemia and indolent HCVrelated B-NHL decreases after HCV eradication, data reinforcing the suggestion of a contribution of chronic antigenic stimulation to the physiopathologic process of HCV B-NHLs [11–13]. Clinically, HCV has been associated with different histotypes of B-cell B-NHLs which are indistinguishable from typical B-NHL, except for the presence of HCV, the coexistence of liver disease, and the presence of cryoglobulinemia. Because indolent HCV B-NHLs are currently considered a progression of MC related to HCV infection, they are treated in the same way as MC with antiviral therapy (such as pegylated interferon and Ribavirin) [14, 15]. New approaches, such as anti-CD20 monoclonal antibody, have also been proposed alone or in addition to antiviral treatment [11, 16]. HCV-B-NHL has been treated like other lymphomas when symptomatic. The strong association between HCV infection and BNHLs has lead to search for molecular signatures that can predict patients’ characteristics, enhance understanding of biological mechanisms of lymphomagenesis, and could have diagnostic/clinical usefulness. 2 This paper takes into account gene expression profiling, characterization of B-cell maturation stages, experimental antigen-induced B-cell growth, and immunoglobulin secretion as well as immune-regulatory molecules involved in these processes, which, taken together, provide powerful means to better define HCV-lymphoma entities. Despite these studies, the identification of the molecular signature of HCV-B-NHLs is not completely defined yet and we underscore the need for further studies. 2. HCV + B-NHL Histotypes HCV infection has been associated with different histotypes. Splenic marginal zone lymphoma (SMZL) is a rare lowgrade B-cell lymphoma (less than 1% of all B-NHLs) but is a commonly found characteristic of HCV infected population, they develop it in about one-third of cases [17, 18]. SMZL displays a strongly homogeneous signature implying the existence of a single molecular entity [19]. Phenotypically, SMZL is usually negative for CD10, CD23, and CD123. They coexpress IgM and IgD, with surface immunoglobulin light chain restriction. Of the genes deregulated in SMZLs, special mention should be made for the genes involved in BCR signaling, tumor necrosis factor signaling, and NF-κB activation [20–22]. A higher prevalence of HCV positivity was also observed among lymphoplasmacytoid/lymphoplasmacytic/immunocytoma and diffuse large cell histotypes than among HCVnegative counterparts [18]. In primary hepatic lymphomas, mainly of DLBCL type, the prevalence of HCV infection is again higher than that in the HCV-negative population [23]. 3. B-Cell Receptor It has been previously demonstrated that the B-cell receptor (BCR) repertoire expressed by clonal B-cells involved with HCV-associated MC as well as with B-NHL is not random, with VH1-69 and VH3 heavy chain and VK3-20 and VK315 light chain genes being the most represented [9]. These data suggest a model of antigen-driven origin for these lymphoproliferative disorders with the recognition of a limited number of HCV antigens, that is, NS3 [24], E2 [9, 25], and indirectly core-antibody complexes [26, 27]. Moreover, core antigens are proposed as responsible for vascular damage [28] and NS3 antigen as responsible for membranoproliferative glomerulonephritis [29, 30]. 4. Pauciclonality of Peripheral B-cells in Both Resolved and Chronic HCV-Infected Patients Pauciclonality of the peripheral B-cell population is a characteristic of HCV-infected patients with MC and/or B-B-NHL [31, 32] and is also a distinguishing feature of subjects who spontaneously resolved HCV infection even though they did not present any clinical manifestation of lymphoproliferative disease [33]. The most important Clinical and Developmental Immunology difference between expanded B-cells of resolved and chronically infected patients has been shown in the B-cell CD27− subpopulation. B-cell clones from patients who are spontaneously resolvers preferentially used similar VH, DH, and JH gene segment (...truncated)