Reevaluating the Association Between Epstein-Barr Virus (EBV) and Breast Cancer in the United States

The World Health Organization estimates 9.9% of cancers are attributable to viruses. Notably, human papillomavirus causes roughly 90% of cervical cancers, while Epstein-Barr virus (EBV) is linked to nearly 10% of gastric carcinomas. Regarding breast cancer, the association with EBV is inconclusive. While studies in some nations report an association, those in the United States largely do not. We reviewed studies from 2003 to 2023 and identified seven that analyzed EBV association with breast cancer in American patients. We observed a potential risk of not investigating novel EBV variants. Detection protocols utilized only lymphoma-derived strains, despite the current knowledge suggesting that genotype variation can influence pathogenic potential and cell tropism. Certain EBV strains, for instance, may preferentially infect epithelial cells and increase the risk of nasopharyngeal carcinoma (NPC) by up to 11 times. Stated simply, the optimal EBV detection protocol for breast cancer cells may differ from lymphoma cells. Reliance on lymphoma-derived strains assumes a level of sequence conservation among EBV genomes. Mounting evidence demonstrates greater variation than previously believed, especially in key coding and non-coding regions. Our analysis reveals that 5/7 (71%) studies used at least one assay sequence that did not exactly match more than 50% of EBV genomes in NCBI GenBank. Moreover, 98% of these GenBank entries became available after assay sequences were selected. Overall, it is possible the current understanding may be incomplete. Should breast cancer mirror gastric carcinoma and exhibit EBV influence in certain subtypes, these insights could enable targeted therapies and screening programs. ObjectivesThis study examines potential limitations of prior investigations into the association between Epstein-Barr Virus (EBV) and breast cancer in the United States. Specifically, our aims are to: O_LIAssess the cellular origin and pathogenicity of EBV strains employed in detection protocols. This objective stems from the background sections discussion on EBV genotype variations and their potential influence on tissue tropism and pathogenic mechanisms. C_LIO_LIEvaluate the sequence similarity between assay sequences and available EBV genomic data. This objective addresses the concern raised in the background section regarding the potential for newfound sequence variation among EBV strains and the implications for accurate detection. C_LIO_LIDetermine the extent to which detection protocols incorporate the latest EBV genomic data. C_LI