Beyond the usual suspects: Emerging associations between Epstein-Barr virus infection/infectious mononucleosis and cancers

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus and a causal factor for Burkitt Lymphoma (BL), Hodgkin Lymphoma (HL), gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC). Whether EBV contributes to a wider spectrum of cancers remains uncertain. We reviewed MEDLINE, Embase and Web of Science on 30th July 2024 to identify observational studies that examined the association between EBV infection or EBV-infectious mononucleosis (IM) and cancers beyond BL, HL, GC and NPC. Evidence was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. For cancers meeting minimum thresholds we assessed etiologic fractions (EFs), biological plausibility, epidemiological burden, latency after IM, and predictive biomarkers. Thirty-three eligible studies were identified, yielding 13 hypotheses (i.e. specific potential reported associations between EBV infection or IM and individual cancer types) that advanced through GRADE. Breast cancer and NHL had the greatest weight of biological plausibility, cervical and prostate the least. Despite an array of tests, testicular cancer studies provided limited evidence. EFs ranged between 12.3% (IM-breast) and 85.1% (EBV infection-NHL). Breast and prostate cancers had the highest global incidence. Only one study (for NHL) provided data on time from IM to cancer onset, and prostate-specific antigen was the only biomarker identified. In this review, we highlight eight cancers across six cancer groups (breast, cervical, leukaemia/other haematologic, NHL, prostate, testicular) with some evidence of EBV involvement. These results reinforce the potential long-term value of EBV vaccine development, while emphasising the need for high-quality prospective studies with robust methods of viral detection to establish causality