EARLY DETECTION
unbalancing signal transduction, may be used by these of HIV-infected individuals, as there is still a lack of widespread
pathogens and determine transformation. In addition, viruses antiretroviral therapy in Africa where AIDS is epidemic and
may also encode products, which may mimic cellular proteins HIV continues to spread. Better tools for detection and better
(i.e. v-cyclins), thus disturbing mechanisms of cell cycle regimens for management of these malignancies are
regulation. This leads to the concept that a complex interplay necessary. Moreover, a better understanding on how
between viruses and the host cell machinery does exist. infections by these viral agents can lead to tumors will lead to
Epidemiologic differences have been accounted for the development of methods to enhance the immune response
lymphomas and the substantial differences in incidence to control these agents as well as development of therapeutic
patterns among the lymphoid neoplasms may suggest that agents to treat these malignancies. A strong association with
5
there is an etiologic heterogeneity by disease subtype . the human herpesvirus-8 and lymphomas has also been
A good example of how infectious agents and environmental described in HIV-positive patients11,12.
factors may participate in lymphomagenesis is offered by the Therefore it is crucial performing research in developing
endemic form of BL, as both malaria and the EBV are thought countries trying to highlight environmental factors which may
to have an important role for this malignancy. Endemic BL is act as risk factors in such settings. Large multinational
almost universally associated with infection of Epstein-Barr, pharmaceutical and biochemical companies could underwrite
though co-infection with malaria also appears to be important the costs of programmes such as this if convinced that the
in the pathogenesis of BL. Acute malaria infection inhibits developing world represents a potential future market for
EBV-specific immune responses and leads to an increase in the them. We have demonstrated the feasibility of this by
number of EBV-carrying B-cells in the circulation6. The pattern collaboration with several African institutions in the
of malaria infection appears to be important in performance of several research projects in which have
lymphomagenesis. Holoendemic, or perennial and intense African colleagues have been actively involved. A number of
transmission of malaria, appears to induce much higher young African doctors have, as a result, been enrolled in a PhD
circulating EBV viral loads than sporadic transmission of programme at our institution in Italy.
7
malaria or no transmission of malaria . This immune
dysregulation probably contributes to the pathogenesis of BL Research achievements in collaboration with
and explains why EBV-related BL occurs with a much higher African institutions: An overview
frequency in areas where malaria is common and malaria Understanding the genetics of Burkitt lymphoma
infection is more intense. Despite the recurrent studies on this Earlier studies from our group, in collaboration with African
association, there is still no conclusion as to the exact colleagues, revealed that differences exist between endemic
mechanisms, and no practical approaches have been (eBL) and sporadic BL (sBL), especially in terms of mitotic and
developed to de-link the two pathogens in order to prevent apoptotic indexes (MI, AI) and in the association with EBV13.
disease occurrence8. Significant spatial clustering of elevated These collaborations allowed the detailed characterization of
eBL risk in high-malaria transmission regions and its reduced BL at the genetic level, which revealed that eBL and sBL cases
incidence where malaria is infrequent definitely suggests that carry mutations in a gene belonging to the retinoblastoma
malaria plays a role in the complex eBL etiology, but additional family of proteins, the RBL2 gene14, whereas no mutations
factors may also be likely involved9. Other agents have been were detected in the AIDS-related BL variant. This
proposed as cofactors in BL lymphomagenesis, including observation led to the identification of a novel mechanism of
arboviruses and plant extracts commonly used in traditional inactivation of this member of the retinoblastoma family by
medicine, which can explain the shifting foci and space-time the HIV-encoded Tat protein through the physical binding of
10
clusters of the lymphoma observed in endemic regions . Tat to the pRb2/p130 protein and subsequent inactivation15,16.
Due to the high spread of the AIDS epidemics in Africa, the In a later study a signature downstream the RBL2/p130 gene
role of HIV in lymphomagenesis is quite important, as HIV was identified as relevantly altered in endemic Burkitt
infection is often detected in NHL. Three major factors lymphoma cell lines and primary tumors17. A percentage of BL
promoting the development of lymphoma are HIV-induced cases (about 10%) have been shown to lack MYC
immunosuppression, chronic antigenic stimulation, and translocations, suggesting that alternative methods to
cytokine over-production. Though the introduction of highly translocation may sometimes be responsible for the up-
active antiretroviral therapy has changed the epidemiology of regulation of the c-MYC protein. We have shown this to be
AIDS-related lymphomas, it is likely that AIDS-associated the case in a study involving a recently described class of small
malignancies will continue to be a major clinical manifestation non-coding RNAs, the microRNAs (miRNAs)18,19.
78 CANCER CONTROL 2013