Hepatitis B and C Virus Infection and Risk of Haematological Malignancies

Aldo Marrone; Marco Ciotti; Luca Rinaldi; Luigi Elio Adinolfi; Marc Ghany


J Viral Hepat. 2019;27(1):4-12. 

In This Article

Oncogenic (Mechanisms): Role of HCV and HBV in Lymphoproliferative Disorders

Oncogenic Role of HCV in Lymphoproliferative Disorders

HCV and Mixed Cryoglobulinemia. The development and evolution of EMC only in a proportion of HCV chronic patients suggests that other factors beyond HCV infection plays a role in this nonmalignant lymphoproliferative disorder. This notion is supported by several observations such as the lack of an association of specific viral variants with the disease; the different prevalence between ethnic groups suggesting that genetic, epigenetic and individual determinants may play a role in the pathogenesis of this disease and the association of specific HLA patterns with the development of EMC.[60–62]

Recently, the role of miRNAs has been investigated in several human diseases. miRNAs are short oligoribonucleotides, 19–25 bases long, that control the expression of genes by blocking the translation of complimentary mRNAs. A role in the development and regulation of the immune system and in autoimmunity has been suggested.[63,64] A role for miR-122 in regulating HCV replication has been reported,[65] and some miRNA patterns appear dysregulated by HCV in liver cancer.[66] miRNAs may also play a role in the hematopoietic maturation process, and their altered expression is considered critical in the development of some haematological malignancies. For instance, miR155, miR146 and miR26b were shown to be involved in the pathogenesis of different lymphoma subtypes including some HCV-related lymphomas (marginal zone lymphoma and diffuse large B-cell lymphoma).[67–69] In a recent study, the expression profile of some miRNAs (miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155) has been investigated in HCV-infected patients with or without EMC or NHL and in a group of healthy controls.[70] miRNA expression in PBMCs determined by real-time PCR showed a significant increase in miR-21, miR-16 and miR-155 only in NHL patients whereas a significant decrease in miR-26b was detected in both EMC and NHL subjects with HCV when compared to healthy controls. A normalization of miR-26b level was observed in PBMCs of patients who cleared the virus after antiviral therapy. This reversible downregulation of miR-26b suggests that it may have an important role in the pathogenesis of HCV-related lymphoproliferative disorders, and it could be used as a transition marker in these disorders. A target of miR-26b is Nek6 that codes for a kinase involved in the initiation of mitosis. Increased expression of Nek6 has been described in malignant tumours and human cancer cell lines, and it might have a role in tumourogenesis.[68] LEF-1 is another target of Mir-26b. LEF-1 is a nuclear transcription factor that forms a complex with ß-catenenin and T-cell factor and induces transcription of cyclin D1 and c-myc. Overexpression of LEF-1 is associated with downregulation of miR-26b in different cell lines.[71] Elevated levels of LEF-1 have been reported in chronic lymphatic leukaemia,[72] Figure 1.

Figure 1.

Expression patterns of miRNAs in PBMCs of NHL and MC-HCV+ patients. Down-regulation of miR-26b is reported associated to an increased expression of NEK-6 and LEF-1 in human tumours and cancer cell lines

Non-hodgkin Lymphomas. Based on experimental evidence, several mechanisms have been proposed to explain the possible role of HCV in the development of NHL. The HCV E2 glycoprotein is the major antigenic target during HCV infection,[73] and it has been hypothesized that E2 could be one of the antigens responsible for the chronic antigenic stimulation that leads to a selection of a B-cell clone from which NHL originates. This hypothesis has been nicely demonstrated by Re et al[74] who showed in a chronic HCV-infected patient with EMC that the B-cell clone found after development of overt NHL was already present in the bone marrow where it was detected as a non-neoplastic oligoclonal proliferation during the EMC.

The E2 glycoprotein could also activate the tumourgenesis process through its interaction with the tetraspanin CD81 receptor present on B-cells.[75] It has been demonstrated that the binding of CD81 by the E2 induces the preferential proliferation of the naive (CD27) B-cell subset and that the polyclonal proliferation of naive B lymphocytes might favour the development of B lymphocyte disorders associated with HCV chronic infection. Notably, the eradication of infection caused a normalization of the activation-markers expression.[76]

Abnormal cell proliferation induced by HCV is often associated with chromosomal translocations (t(14;18)), overexpression of antiapoptotic genes such as Bcl-2 and immunoglobulin gene rearrangement (IgH).[39,77] Interaction of E2 with CD-81 induces double-stranded DNA breaks specifically in the variable region of immunoglobulin (V(H)) gene loci, leading to hypermutation in the V(H) genes of B-cells and enhanced expression of activation-induced cytidine deaminase (AID),[78] Figure 2.

Figure 2.

Molecular mechanisms involved in the haematological malignancies HBV and HCV related

Direct infection of B-cells could represent another way through which HCV mediates its oncogenic action. There have been conflicting reports on the ability of HCV to infect and replicate in B cells as well as other mononuclear cells.[25,79,80] High levels of CD-81 on the cell surface may be required for productive HCV infection.[81] Co-infection with other viruses could promote HCV replication in infected cells. In this regard, EBV promoted HCV replication in EBV-infected cell clones unlike their uninfected counterparts.[82]

HCV-related Oncogenic Mutations. Machida and co-workers reported that both acute and chronic HCV infection caused a 5- to 10-fold increase in mutation frequency in Ig heavy chain, BCL-6, p53 and ß-catenin genes in in-vitro HCV-infected B-cell lines and HCV-associated peripheral blood mononuclear cells, lymphomas and HCCs. Strikingly, mutated pro-oncogenes were detected in HCV-associated lymphomas and HCCs, but not in lymphomas of nonviral origin or HBV-associated HCC. Induction of error-prone DNA polymerases such as zeta and iota polymerases by HCV and activation-induced cytidine deaminase may contribute to the increase in mutation frequency observed. Taken together, these results suggest that HCV induces a 'mutagenic' phenotype and suggests a 'multistep' mechanism for HCV-induced lymphoid malignacies.[83] This observation was not confirmed by Tucci et al.[84] In this work, the authors attempted to clarify whether HCV has a mutagenic effect on B cells in-vivo and analysed three cancer-related genes, p53, BCL6 and CTNNB1 (ß-catenin) in naïve and memory B cells from the peripheral blood of four patients with chronic HCV infection and intrahepatic B cells from the liver of two HCV-infected patients. No mutations were found in p53 and CTNNB1 genes, while in BCL6 gene, the physiological target of the somatic hypermutation process in germinal centre B cells, the level of mutation was not higher than that reported in B-cell subsets in healthy individuals.

Aberrant hypermutations of the proto-oncogenes PIM1, PAX5, RHOH and MYC have been reported in more than 50% of diffuse, large, B-cell lymphomas. These four hypermutable genes are also susceptible to chromosomal translocations in the same regions, implicating a role for aberrant hypermutation in lymphoid tumourogenesis.[85] However, when the same genes were analysed in tumour biopsies from 32 HCV positive B-cell NHLs, the frequency of aberrant hypermutation was lower than that seen in HCV negative B-cell large diffuse lymphomas[85,86] suggesting that aberrant hypermutation is not the major contributor to malignant trasnformation in B-cell lymphomas associated with HCV.[86] These findings are in line with those of Tucci et al that HCV does not induce a general mutated phenotype in B cells.[84]

Recently, polymorphisms in the promoter of the BAFF gene have been investigated.[87] BAFF (B-cell activating factor) is a B-lymphocyte cytokine for which it has been hypothesized to have a role in the pathogenesis of HCV-related lymphoproliferative disorders. BAFF is essential for development and survival of B-lymphocytes. High serum levels of BAFF have been detected in HCV-positive patients compared with healthy controls, and more frequently in HCV-infected patients who developed lymphoproliferative disorders.[29] A BAFF-871 C/T promoter polymorphism has been found significantly associated with EMC in HCV-positive patients.[87] Finally, elevated serum levels of osteopontin were found in HCV-associated lymphoproliferative disorders.[88]

Oncogenic Role of HBV in Lymphoproliferative Disorders (NHL). Patients sero-positive for HBV are at increased risk of developing NHL as suggested by several meta-analyses and cohort studies. Patients from or living in high HBV endemic regions appear to be at greater risk of developing NHL.[41,89] However, the biological mechanisms underlying the development of this malignancy are not clear. Similarly to lymphoid malignacies induced by HCV, chronic HBV infection might play a role in the genetic alterations (eg translocations) that lead to immunosuppression, cell cycle dysregulation, lack of apoptosis and alteration of the immune processes. It is known that the HBV-X protein targets p53 and nucleotide repair mechanisms and inhibition of p53 can cause abnormal cell division in liver cells favouring the development of HCC.[90,91] A high prevalence of HBV infection has been reported in patients who developed B-cell NHL compared to those who developed T-cell NHL.[92] This finding suggested that HBV may have a pathogenetic role in this subtype of NHL[92,93] and that the virus could dysregulate B-cell proliferation by inhibiting the action of p53 as demonstrated in liver cells,[91,92] Figure 2.

The level of miRNAs has also been investigated in HBV-/HCV-infected patients with indolent B-cell NHL and compared with a control group of HBV-/HCV-negative patients with indolent NHL. miR-30b was found to be increased in HBV-/HCV-positive cases, while miR-92a was decreased in patients negative for these infections. Although differences were observed between the two patient groups, no firm conclusions can be drawn on this association because of the limited data available.[94]