Introduction
In the United States, over 50% of children aged 6–8 and over 90% of adults are infected with the Epstein-Barr virus (EBV), an enveloped, double-stranded DNA gamma-1 herpesvirus. EBV is also known as human herpesvirus 4. It is transmitted mainly by saliva, although transmission via blood is possible. In low- to middle-income countries, infection during infancy occurs at a higher rate than in higher-income countries, where infection may occur later in childhood. EBV-infected B lymphocytes can produce viral proteins, which enable those B lymphocytes to survive and proliferate indefinitely, leading in some cases to cancer.
Methods
The National Toxicology Program (NTP) conducted a cancer hazard evaluation of EBV infection and seven types of cancer for possible listing in the Report on Carcinogens (RoC). The evaluation included the findings from studies reported in the IARC monograph in Volume 100B, as well as from human cancer studies and mechanistic studies and reviews published after the IARC monograph. For each cancer site, the evidence from human and mechanistic studies was integrated considering the following guidelines: Hill’s characteristics of causality, multicausality epidemiology considerations, guidance from the IARC 100B working group, and concepts of direct and indirect carcinogenesis proposed several virus experts. Finally, the RoC’s listing criteria were applied to the assessment to reach an overall cancer hazard conclusion.
Results and discussion
NTP concluded there was sufficient evidence of the carcinogenicity of EBV for six cancers. Four are lymphomas arising from immune cells: Burkitt lymphoma (endemic), Hodgkin lymphoma, immune-suppression-related non-Hodgkin lymphoma (NHL), and extranodal NK/T cell lymphoma (nasal type). Two are cancers arising from epithelial cells: nasopharyngeal carcinoma and stomach (gastric) cancer. Evidence of carcinogenicity is based on the collective evidence from human epidemiological and clinical cancer studies, as well as molecular studies of human tissue.
For endemic Burkitt lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma, statistically significant increased risks were found in case-control and cohort studies in different populations. A key event in Burkitt lymphoma is a chromosomal translocation of c-myc to an immunoglobin gene promoter leading to proliferation and growth of B lymphocytes. EBV-infected stomach tumors have a unique molecular profile.
Evidence that EBV is associated with immunosupression-related NHL, extranodal NK/T cell lymphoma (nasal type), and gastric cancers comes from case series data with large numbers of cases, clinical studies, or a few case-control or nested case-control studies. Limited evidence was found for sporadic Burkitt lymphoma due to the small number of cases in the studies and moderate, nonsignificant increased risk.
Molecular studies in humans for all cancer demonstrated that the EBV-related tumors were monoclonal, which provides evidence that infection preceding the cancer contained a high percentage of EBV DNA and expressed oncogenic EBV proteins. Mechanistic studies found that EBV can transform human B lymphocytes into permanently infected lymphoblastoid cell lines in culture.
NTP hazard conclusion and significance
The conclusion of the cancer hazard evaluation was that EBV should be listed as known to be a human carcinogen in the RoC. The Secretary of Health and Human Services approved the listing of EBV in the 14th RoC. The rationale for the listing was sufficient evidence from studies in humans (epidemiological and molecular) for six types of cancer. Globally, EBV is estimated to be responsible for 200,000 cancers per year.
National Toxicology Program (NTP). 2016. Report on Carcinogens monograph on Epstein-Barr virus. Research Triangle Park, NC: National Toxicology Program. RoC Monograph 07. https://doi.org/10.22427/ROC-MGRAPH-07