Research Article: A Role for RNA Viruses in the Pathogenesis of Burkitt’s Lymphoma: The Need for Reappraisal

Date Published: November 29, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Corry van den Bosch.


Certain infectious agents are associated with lymphomas, but the strength of the association varies geographically, suggesting that local environmental factors make important contributions to lymphomagenesis. Endemic Burkitt’s Lymphoma has well-defined environmental requirements making it particularly suitable for research into local environmental factors. The Epstein-Barr virus and holoendemic Malaria are recognized as important cofactors in endemic Burkitt’s Lymphoma and their contributions are discussed. Additionally, infection with Chikungunya Fever, a potentially oncogenic arbovirus, was associated with the onset of endemic Burkitt’s Lymphoma in one study and also with space-time case clusters of the lymphoma. Chikungunya Virus has several characteristics typical of oncogenic viruses. The Flavivirus, Hepatitis C, a Class 1 Human Carcinogen, closely related to the arboviruses, Yellow Fever, and Dengue, is also more distantly related to Chikungunya Virus. The mechanisms of oncogenesis believed to operate in Hepatitis C lymphomagenesis are discussed, as is their potential applicability to Chikungunya Virus.

Partial Text

It has been estimated that approximately 20% of all cancers, worldwide, are attributable to infectious agents [1]. This is likely to be an underestimate because of under-reporting and under-ascertainment, particularly in resource-poor countries, where the burden of infection-related cancers is almost four times that of the more prosperous countries [1]. A number of infectious agents, comprised of a variety of different types of organisms, have been shown to be associated with lymphomas. It is highly probable that this number will continue to expand as diagnostic methods improve, new organisms emerge and general advances in knowledge are made.

Burkitt’s Lymphoma (BL), an aggressive non-Hodgkins Lymphoma (NHL), has an extremely rapid doubling time of 24–48 hours as almost all the cells are cycling at one time [23]. It has been calculated, based on the phenomena of seasonality and time-space case clusters sometimes observed in the endemic form of Burkitt’s Lymphoma (eBL), that the latent period for this lymphoma is likely to be as short as one year [24]. The rapid growth, coupled with a short induction period could, theoretically, make the train of events involved in lymphomagenesis easier to unravel.

Arboviruses occur world-wide, particularly in the tropics and where vector-control is poor. They are an important group of diseases, with considerable economic consequences for the livestock industry [115], and a considerable burden of morbidity and mortality in humans [115, 116] although human disease is too often unrecognized or misdiagnosed [116, 117], except when large-scale epidemics occur as with the frequent outbreaks of Dengue in South-East Asia [118], or the recent CHIKV epidemic in the Indian Ocean [93]. Climatic conditions are important in determining arboviral outbreaks, with rainfall pattern, temperature, and humidity all playing a role [118].

It has already been mentioned that the Flavivirus, HCV, a Class 1 Human Carcinogen [5] is most closely related not only to Hepatitis G, another apparently oncogenic Flavivirus, but also to the Arboviruses, Yellow Fever, and Dengue [153–156]. Hepatitis G accounts for up to 9% of all NHLs in some studies, showing a stronger association with lymphomas than HCV in several studies [157, 158].

HCV is part of the Family Flaviviridae to which those Arborviruses which are Flaviviruses belong. The arboviruses most closely related to HCV are the Flaviviruses Yellow Fever and Dengue. CHIKV is an Alphavirus, belonging to the Togaviridae Family. Flaviviruses are closely related to Alphaviruses, being previously classified as an Alphavirus subgroup, and were only allocated their own family when sufficient differences were noted [153]. It is conceivable that CHIKV, already known to be potentially oncogenic [137, 139] and additionally those arboviruses, closely related to HCV such as Yellow Fever, might deploy oncogenic mechanisms similar to those of HCV because of their shared characteristics, and that some, or all, related Flaviviruses and Alphaviruses could share such potential.

A role in lymphomagenesis has been confirmed for HCV [5] and is probable for Hepatitis G [158], suggesting that closely related flaviviruses, such as Yellow fever, and other related groups of arboviruses, could also have lymphomagenic potential. CHIKV is already known to have oncogenic potential [137, 139]. High levels of CHIKV activity were documented around the time when space-time case clusters of eBL were occurring in Malawi [105], and there was a statistically significant association between recent infection with that virus and the onset of eBL [12, 22]. High levels of CHIKV activity were also recorded in NW Cameroon [203] around the time when extremely high rates of eBL were recorded, up to 20/100,000, and spatial clusters were observed [100]. Although no analysis for space-time clustering was performed in Cameroon, it is likely that this was occurring, particularly in one area where the spatial clustering was very pronounced. In addition, the early space-time case clusters recorded in Uganda occurred at a time when epidemic CHIKV [114] and O’nyong-Nyong Virus activity was observed [200, 202]. O’nyong-nyong, like CHIKV, is an Alphavirus and is antigenically extremely closely related to CHIKV [112]. It could appear that not only CHIKV, but possibly both viruses, could be linked with the eBL case clusters seen contemporaneously with their epidemics. It is also possible that CHIKV could have acted as a cofactor for late-stage eBL pathogenesis, in view of the link between recent CHIKV infection and the onset of eBL recorded in Malaŵi [12, 22].




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