Locus-specific human endogenous retroviruses reveal lymphoma subtypes

The heterogeneity of cancers is driven by diverse mechanisms underlying oncogenesis such as differential 'cell-of-origin' progenitors, mutagenesis, and viral infections. Classification of B cell lymphomas has been defined by considering these characteristics. However, the expression and contribution of endogenous retroelements (EREs) to B cell lymphoma oncogenesis or classification have been overlooked. We hypothesized that incorporating ERE expression signatures would increase the resolution of B cell identity during healthy and malignant conditions. Here, we present the first comprehensive, locus-specific characterization of ERE expression in benign germinal center B cells, diffuse large B cell lymphoma, Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt lymphoma, and follicular lymphoma. Our findings demonstrate unique human ERE signatures in the GC and lymphoma subtypes whose activity can be used in combination with gene expression to define B cell lineage in lymphoid malignancies, highlighting the potential of ERE analyses as a tool in lymphoma classification, diagnosis, and the identification of treatment groups.