Risk factors for Epstein Barr virus-associated cancers: A systematic review, critical appraisal, and mapping of the epidemiological evidence

Background Epstein Barr Virus (EBV) infects 90%-95% of all adults globally and causes ~ 1% of all cancers. Differing proportions of Burkitt's lymphoma (BL), gastric carcinoma (GC), Hodgkin's lymphoma (HL) and nasopharyngeal carcinoma (NPC) are associated with EBV. We sought to systematically review the global epidemiological evidence for risk factors that (in addition to EBV) contribute to the development of the EBV-associated forms of these cancers, assess the quality of the evidence, and compare and contrast the cancers. Methods MEDLINE, Embase and Web of Science were searched for studies of risk factors for EBV-associated BL, GC, HL and NPC without language or temporal restrictions. Studies were excluded if there was no cancer-free comparator group or where analyses of risk factors were inadequately documented. After screening and reference list searching, data were extracted into standardised spreadsheets and quality assessed. Due to heterogeneity, a narrative synthesis was undertaken. Results 9916 hits were retrieved. 271 papers were retained: two BL, 24 HL, one GC and 244 NPC. The majority of studies were from China, North America and Western Europe. Risk factors were categorised as dietary, environmental/non-dietary, human genetic, and infection and clinical. Anti-EBV antibody load was associated with EBV-associated GC and BL. Although the evidence could be inconsistent, HLA-A alleles, smoking, infectious mononucleosis and potentially other infections were risk factors for EBV-associated HL. Rancid dairy products; anti-EBV antibody and EBV DNA load; history of chronic ear, nose and/or throat conditions; herbal medicine use; family history; and human genetics were risk factors for NPC. Fresh fruit and vegetable and tea consumption may be protective against NPC. Conclusions Many epidemiological studies of risk factors in addition to EBV for the EBV-associated forms of BL, GC, HL and NPC have been undertaken, but there is a dearth of evidence for GC and BL. Available evidence is of variable quality. The aetiology of EBV-associated cancers likely results from a complex intersection of genetic, clinical, environmental and dietary factors, which is difficult to assess with observational studies. Large, carefully designed, studies need to be strategically undertaken to harmonise and clarify the evidence.