Global burden of deaths from Epstein-Barr virus attributable malignancies 1990-2010

Cancer is one of the leading causes of death worldwide and research focused on understanding the etiology and pathogenesis of cancer is a major challenge. It has previously been estimated that oncogenic viruses play an etiological role in the development of approximately 12% of all human malignancies [1, 2]. The vast majority of these malignancies are caused by just five different viruses of which Epstein-Barr virus (EBV) is arguably one of the most extensively studied [3].

EBV is a large dsDNA lymphotropic herpesvirus historically associated with Burkitt’s lymphoma, from which the virus was first isolated 50 years ago [4]. However, ever since its isolation, EBV has continued to attract considerable attention, primarily due to its oncogenic properties and its association with a number of human malignancies, including Burkitt’s lymphoma (BL), nasopharyngeal carcinoma (NPC), post-transplant lymphoproliferative disease (PTLD), Hodgkin’s lymphoma (HL) and gastric carcinoma (GC) [3]. EBV is primarily transmitted via saliva and in healthy immunocompetent individuals it infects and establishes life-long latency in memory B-lymphocytes [5, 6]. In these cells, the virus limits its gene expression to 1 or 2 viral proteins only, thus escaping the immune surveillance [7]. This is referred to as type 0/1 latency. In some EBV-associated malignancies, such as NPC and HL, at least 3 viral genes have been shown to be expressed, including the oncogenic membrane protein LMP-1 [3]. This is referred to as type 2 latency. How the viral infected cells in these malignancies escape the immune system is unclear. In contrast, in vitro infection of B-lymphocytes results in their immortalization and establishment of lymphoblastoid cell lines (LCLs) [8]. In these cells, at least a dozen different EBV latent products are expressed, including 6 Epstein-Barr nuclear antigens (EBNAs), 3 latent membrane proteins (LMPs) and 2 non-protein coding small RNAs (EBERs) [3]. In addition to these, a number of micro-RNAs have also been shown to be expressed [9]. This is referred to as type 3 latency or growth program [10, 11]. A substantial body of evidence indicates that a number of these latent viral products are central for EBV-induced immortalization of the infected cells. In EBV-associated malignancies, all three patterns of latency have been detected, suggesting that EBV induces oncogenesis by different mechanisms in different malignancies. Although EBV is carried asymptomatically by over 90% of adults worldwide, induction of cancer by this virus is nevertheless a very rare event. This clearly indicates that EBV on its own is not sufficient and other co-factors are necessary [12‐14]. Thus, in order to link EBV in the etiology of a malignancy it is essential to demonstrate the presence of viral genome and/or gene expression directly in the tumor cells. This approach has revealed that the virus is not necessarily etiologically involved in all cases of a malignancy with which EBV has been implicated [15, 16]. For example, only about 40% of Hodgkin’s lymphoma cases have EBV in the malignant cells and the prevalence varies with age [17].

In this study we provide the most up-to-date and detailed descriptive epidemiology of EBV-attributable malignancies using the Global Burden of Disease, Injuries and Risk Factors Study 2010 (GBD 2010) dataset. GBD 2010 is the largest and most comprehensive study ever conducted to measure the global health metrics [18, 19]. As far as we are aware, the present study is the first to use GBD 2010 data to estimate the burden of EBV-associated malignancies in different age and sex groups in 21 world geographical regions from 1990 to 2010. It is hoped that the findings of this study will high-light the need for potential preventative measures and the global regions where implementation of such measures would have the greatest impact.

Epstein-Barr virus is a well-recognized carcinogen implicated in the etiology of several malignancies of both epithelial and lymphoid origin. In this study, we present descriptive epidemiology of EBV-attributable malignancies using the GBD 2010 data. In contrast to previous studies [1, 2, 55], we focused exclusively on EBV-attributable cancers with an aim to provide an in-depth analysis of the malignancies associated with this virus. In addition to NPC, BL and HL, the current report also includes mortalities from GC and PTLD, both of which are known to be associated with EBV [42, 56, 57]. In this analysis, we present the global burden of mortality from EBV-attributed malignancies, stratified by age, sex and geographical region from 1990-2010. The results of this study demonstrate that the global burden of mortality from EBV-attributed malignancies accounts for 1.8% of all cancer deaths in 2010. This is a 14.6% increase from 1990 and the trends indicate that this burden will continue to increase as the world population and life-expectancy increase [37]. Gastric cancer and NPC accounted for 92% (132,199 cases) of all EBV-attributed cancer deaths, with the vast majority occurring in developing countries, in particular East Asia. Indeed, the age-standardized rates of both of these malignancies are also considerably higher in East Asia compared to western countries, consistent with previous reports [58, 59]. The reason for this elevated incidence in certain Asian countries remains unknown, as does the male preponderance [58]. Epidemiological studies on NPC and GC have shown that individuals who migrate from high-risk countries to low-risk countries have incidence rates intermediate to their Country of origin and their host Country [53, 59]. This implies that the etiology of these malignancies is complex and most probably involves multiple factors including, environmental, genetic and dietary. One factor in particular, namely EBV, has been consistently shown to be involved in the development of these malignancies [53, 56, 60], but the molecular mechanism(s) involved is not well understood. The fact that virtually all adults worldwide are infected with EBV, and yet only a very small fraction of individuals actually develop these malignancies, clearly indicates that EBV alone is not sufficient. For NPC, it has been hypothesized that infection with EBV early in childhood, which is typical of high-incidence regions, is important [53]. For GC, in particular non-cardia type, Helicobacter pylori is generally accepted to be one of the prime risk factors [61, 62]. Of the dietary and life style factors, increased intake of salts or salt preserved food, alcohol and smoking have been implicated, although the attributable risk is at best only modest [53, 63, 64].

In contrast to NPC and GC, the role of EBV in the development of BL, PTLD and HL is to some extent better understood. Burkitt’s lymphoma is primarily a childhood malignancy endemic in Sub-Saharan Africa. Three factors have been shown to be important in the development of this malignancy: EBV, malaria and deregulated activation of the c-myc oncogene [65]. In the case of PTLD, EBV is thought to be the primary driving force. EBV infected cells express several viral latent products [66, 67], including the viral oncogene LMP-1 [68]. These cells would normally be eliminated by the immune system, but in immunocompromised individuals such as transplant recipients, the infected cells proliferate unchecked. Reversal of immunosuppression or infusion of EBV-specific cytotoxic T-cells can prevent the development of PTLD [69, 70]. In HL, there is restricted EBV-gene expression in the malignant cells, but crucially LMP-1 is expressed [71] and thought to be central in the oncogenic process [72].

Although this study presents the most comprehensive and most up-to-date estimates of the global mortalities from EBV-associated malignancies, it has several limitations inherent in any study of this kind. First, our estimates rely on the accuracy of the dataset from the GBD 2010 study. GBD 2010 is the largest and most comprehensive project ever conducted to measure global health metrics and as expected, this ‘super-human’ effort had its own limitations which have been described in detail elsewhere [19, 37, 38]. Second, in calculating the mortality of EBV-attributable fraction of NPC, GC, HL, BL and PTLD, it was assumed that the risk of death from EBV-positive and negative cases is the same. This may not always be the case for all EBV-associated malignancies [25, 28, 73]. Indeed, some studies have reported a better prognosis for EBV-positive cases compared to negative cases [25, 74]. Third, to calculate the mortality of EBV-attributable cases of BL, we first had to determine the number of deaths from BL, as this was not directly available from GBD 2010 data. In the GBD 2010 data, BL was grouped in the larger category of non-Hodgkin’s lymphoma (NHL). In calculating the mortality of BL, it was assumed that the mortality of BL was the same as other lymphomas in the NHL group. Once again, this assumption is strictly speaking not true, since NHL represent a heterogeneous group of lymphomas with differing prognoses [75]. Fifth, for calculating the proportion of EBV-attributable malignancies at different time points i.e. 1990, 1995, 2000 and 2005, we used EBV-attributable proportions of 97.2% for NPC, 80% for PTLD, 51.2% for BL, 44.7% for HL and 9.2% for GC, estimated for 2010, with the assumption that these proportions have not changed over time. Finally, our estimate of 142,979 global deaths from EBV-associated malignancies is likely to be an underestimate since a few other EBV-associated malignancies such as central nervous system malignancies occurring in AIDS patients, for which there is substantial evidence for causality [76] have not been considered in this analysis.

Cancer is amongst the leading causes of death. In 2010, cancer accounted for 7.978 million deaths, and this figure appears to be rising at a rate of approximately 2% per year [38]. Thus, understanding the risk factors or causes of cancer is of paramount importance for any future prevention strategies. The analysis presented here indicates that 1.8% of all cancer deaths in 2010 were associated with EBV. This is a sizable number of deaths and developing an effective vaccine would not only reduce this burden, but could also prevent infectious mononucleosis, which is also known to be caused by EBV [77].