Discussion
The strength of evidence in the current literature for an association between anti-EBV antibody titers and risk of EBV-associated malignancies differs according to cancer diagnosis. Having elevated levels of anti-EBV IgA antibodies is related to the development of incident NPC. Although the examination of IgA antibodies is limited in relation to HL, the evidence for a link between anti-EBV IgG antibody titers and HL risk is strong. The evidence presented for elevated VCA IgG response and BL status was consistent; however, sample sizes were limited in 2 of the 4 reviewed studies, and the other 2 utilized hospital-based controls, a potentially biased comparison group. Data for GC are inconsistent, with some evidence observed for a link between the anti-VCA response and EBV-positive gastric tumors. Finally, for NHL, half of the studies reviewed reported null results, although some prospective data indicate that the presence of altered anti-EBV antibodies may be important for certain subtypes of NHL.
Although evidence for an association between elevated IgA antibody titers and NPC risk is strong, IgA antibodies against only 3 EBV proteins (EBNA1, VCA, and EA) have been consistently investigated in NPC studies to date. We observed that this same set of 3 proteins represented the universe of investigated EBV targets in the available literature for the other EBV-associated malignancies. This comprises only a small fraction of the approximately 100 open reading frames for EBV, meaning that little comprehensive investigation of EBV serological patterns has been conducted. The technology to explore antibody patterns and investigate responses to multiple peptides simultaneously is available. For example, one of the BL studies reviewed here utilized multiplex bead technology to quantitate the response to multiple peptides in a single assay. Expanding on the number of antigens evaluated could deepen our understanding of the role of the immune response to EBV in the development of these cancers. If it is consistently demonstrated that IgA antibodies are preferentially important for NPC, whereas IgG antibodies are preferentially important for HL, this might reinforce the notion that control of lytic replication at mucosal epithelial surfaces is an important predictor for NPC, whereas the expansion of the EBV-infected B-cell pool is crucial for HL.
Results from lymphoma work reviewed here support the importance of investigating not just individual antibody titers but also patterns of the humoral immune response to EBV. Elevations of specific antibodies years before disease onset may support a direct oncogenic role for EBV in certain cancers, but altered antibody patterns close to the time of diagnosis could reflect a higher prevalence of impaired immunity in persons who develop these malignancies. Both alternatives deserve further evaluation.
Beyond etiological insights, the link between anti-EBV antibodies and disease risk may ultimately translate into biomarkers that can identify persons who are more likely to develop disease. Although it is premature to consider using EBV serological markers for population-level cancer prevention efforts, an endeavor that may never be justified for certain EBV-associated cancers with low incidence or small percentages of EBV-related disease, in at least one case what we have learned about etiologies of these cancers can be applied toward prevention efforts. Measurement of IgA antibody levels has been used in a large, general-population NPC screening demonstration project conducted in a high-risk region of China. Studies conducted in this region during the 1980s found rates of NPC among those that screened positive for VCA IgA that were approximately 40 times higher than those observed in the cohort at large. Unfortunately, these early efforts were not carefully controlled and do not permit accurate quantification of the potential impact of EBV serology–based screening on detection or mortality rates of NPC. Since that time, enzyme-linked immunosorbent assay methods that are cheaper and easier to standardize than the immunofluorescence tests used in the 1980s have become available. Current work in this region of China is ongoing to evaluate the utility of IgA antibodies against VCA and EBNA1 as screening biomarkers, which will in turn allow us to evaluate whether implementation of EBV serology–based screening can decrease the NPC mortality rate.
Our findings suggest that the relationship between the antibody response to EBV and the risk of developing EBV-associated tumors is not well characterized for at least 3 of the 5 cancers reviewed. The results from studies of the different types of cancer often conflict, evaluate antibodies against a limited number of EBV proteins, or fail to investigate multiple antibody types (e.g., IgG and IgA), thereby limiting our ability to draw definitive conclusions about the role of the humoral immune response to EBV in predicting disease risk. However, the available evidence does point to an association between EBV serological patterns and risk for certain cancers, and the availability of reproducible and affordable technology to measure antibody levels presents us with an opportunity to elucidate the role of the humoral immune response to EBV in cancer etiology and prevention moving forward.