Concurrent Infection with Epstein-Barrs Virus as a risk modifier for hepatocellular cancer in Hepatitis C seropositive Patients , study outline
EBV infection has been implicated in the pathogenesis of Nasopharyngeal carcinoma (IARC 1997). More than 80% of NPC patients have high antibody titres to the viral Capsid Antigen VCA-IgG (Henle et al 1973).
Also, antibody to the Early Antigens (EA) is elevated in the diffuse form and the level of these antibodies increases as the stages of the disease progress (Henle at al 1977). Evidence of EBV in NPC tissue has also been found regularly in biopsies including carcinoma in situ by several molecular techniques (wolf et al 1973, Klein et al 1974, Pagano et al 1975, Yeung et al 1993).
EBV infection is endemically present in Egypt and other parts of Africa. Nasopharyngeal carcinoma occurs worldwide with varying incidence rates. It is quite rare in some populations. Incidence of NPC in Egypt is relatively high and may be mapped to the endemicity of EBV, among other factors. However, the highest incidence occurs in the Far East, primarily in persons of Chinese decent (De The at al 1989).
Likewise, the incidence of HCC is remarkably high in the same two populations. Cases reported from China represent half the global burden of HCC (Globocan 2000).
Again, in both populations HCV infection shows high prevalence. In both malignant conditions, only a small proportion of patients infected with the oncogenic virus will eventually develop the malignancy (Evans and Muller 1990).
The similarity of the incidence and prevalence rates of these cancers and their oncogenic viral precursors in the same two populations raises questions regarding the common epidemiological features of these two populations that are not present in other populations and that may be contributing to those incidence profiles for HCC and NPC. Additionally, it raises questions regarding a possible association between EBV infection and HCV related HCC.
The literature presents evidence of the association of EBV with a surprising array of tumours . In the opinion of some researchers, not all these detected associations will prove to be valid. Some of them, as in the association of EBV with stomach cancer appear to be stronger and more valid than others as in the case of breast cancer (Mueller et al 2006).
However, because EBV is a lymphotropic virus that has evolved a variety of oncogenic mechanisms that ensure its survival e.g. the ability to insert itself into the host cell genome and triggering polyclonal expansion of B lymphocytes, the production of LMP1 protein which is an efficient oncogene that plays a role in the upregulation of a range of cellular factors including NFKB transcriptional pathway, it is reasonable to hypothesize that its association with a number of other cancers is immune mediated. In the specific case of HCC, our hypothesis is that EBV infection may acts as an effect modifier of chronic HCV infection whereby people infected with both HCV and EBV are more likely to develop HCC.
The mechanism by which this happens may be a systemic immune effect or an interaction between the two oncogenic viruses in local tissues. A paradigm of cytokine mediated immune function is useful in this setting. In either case, the presence of such an association needs to be investigated as a primary aim with the theory of immune mechanisms examined in an exploratory analysis to generate a valid hypothesis for the next stage of this research proposal if an association is found.
A similar hypothesis was presented by a research group from China in 2000 (Sugawara et al 2000) when they examined the EBV load in hepatocellular carcinoma (HCC) tissues from HCV antibody-positive patients. Their study was conducted on 168 patients and is subject to some criticism in terms of its design.
However, the association is worth following up and the study is most likely to be able to detect a true effect, if it exists, if conducted in the specific populations where these two oncogenic viruses are abundant.