EBV and NPC carcinogenesis—an alternative viewpoint

© Annals of Nasopharynx Cancer. All rights reserved. Ann Nasopharynx Cancer 2021;5:4 | https://dx.doi.org/10.21037/anpc-21-1 The etiology of nasopharyngeal carcinoma (NPC) has been causally linked to environmental and ethnic factors. In this article, we aim to put forward a proposed mechanism linking Epstein Barr Virus (EBV) infection to the observed ethnic and geographical distributions of this unique disease. Primary nasopharynx epithelial cells show very low EBV infection efficiency. A pertinent question in the etiology of NPC would be how and when EBV enters the host cell in NPC patients. Studies on the mouse gamma herpesvirus 68 suggest there is a temporal relationship between the period in life that infection occurs and the subsequent disease that develops. Infection occurring during the neonatal period of the mouse results in respiratory epithelial infection, whereas infection in the adult mouse results in an “infectious mononucleosis” like syndrome (1). Similarly, in humans, EBV infection appear to occur early in life in the susceptible populations for NPC (Southern China, Southeast Asia); whereas in populations with low incidence of NPC (such as in Caucasians), EBV infections occur later in the teens. Incidentally however, this later onset of EBV infection appears to be associated with a higher incidence and a bimodal peak of EBV-related Hodgkin’s Lymphoma in these populations. Of further note, in cities like Hong Kong and Singapore, where the incidence of NPC has been in decline in the last few decades, the incidence of Hodgkin’s Lymphoma in those 2 cities is slowly picking up and beginning to mimic the bimodal peak found in the Caucasian countries (2). Other infection-related cancers like Hepatitis B-associated hepatocellular carcinoma (HCC), H. pylori related gastric carcinoma (GC) and even Merkel cell polyomavirus related Merkel Cell Carcinomas have in common either perinatal, neonatal or early infections. We put forward that a similar mechanism may be at play here, and suggest a postulated mechanism for how EBV might enter the epithelial cell during the neonatal period, giving rise to a chain of events that ultimately results in the carcinogenesis of NPC. Periods of severe aridity between 135,000 and 75,000 years ago in East Africa are believed to be the impetus for human migration out of Africa (3). By about 50,000 to 40,000 years before present (ybp), some were thought to have arrived in Central Asia and settled there. Changes in climatic conditions with the glacial maximum made life difficult again and caused further dispersal. To the east were the insurmountable Pamir and Himalayan mountain ranges, so this forced those who moved east to skirt along the foothills of the Himalayas (in the narrow corridor of present-day Nepal), as they migrated in search of more hospitable environments (Figure 1). But these foothills were also holo-endemic for malaria (right until the time of the British, when they eliminated malaria) (4). This malady is particularly fatal amongst children, who are prone to developing cerebral malaria—and the cause of death is not from the parasite itself, but the immune response to it. We speculate that perhaps malaria selected for a phenotype that had an attenuated immune response to cerebral malaria. Toll like receptor (TLR)-8 which has unique polymorphisms found only in East Asians (5), is a frontrunner. It is the most selected of all the TLRs (6), and is also the only TLR, which is mature during the neonatal period (7). In mice (which do not have a functioning TLR8), loss of TLR7 (which is very similar to TLR8) alters cytokine production and protects against cerebral malaria (8). For those who survived this malaria bottleneck, they emerged from the area in current Northeast India into East Asia (9,10) (Figure 2), bringing with them the new TLR8 polymorphism that had Editorial