Epstein-Barr Virus-Positive Cancers Show Altered B-Cell Clonality

Abstract

Around 20% of human cancers are associated with viruses. Epstein-Barr virus (EBV) contributes to gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. We assessed the prevalence of EBV in RNA-seq from 32 tumor types in the Cancer Genome Atlas Project (TCGA) and found EBV to be present in >5% of samples in 12 tumor types. EBV infects epithelial cells and B cells and in B cells causes proliferation. We hypothesized that the low expression of EBV in most of the tumor types was due to infiltration of B cells into the tumor. The increase in B-cell abundance and diversity in subjects where EBV was detected in the tumors strengthens this hypothesis. Overall, we found that EBV was associated with an increased and altered immune response. This result is not evidence of causality, but a potential novel biomarker for tumor immune status.

High-Throughput Sequence Analysis of Peripheral T-Cell Lymphomas Indicates Subtype-Specific Viral Gene Expression Patterns and Immune Cell Microenvironments

“…To limit false-positive calls related to contamination (54) or low-level virus presence in a small percentage of stromal cells, we utilized a threshold frequency of 0.2 read per million mapped human reads (RPMHRs). This cutoff is in rough agreement with that used in previous investigations by our group and others assessing exogenous viruses in sequencing data (52, 55–57).…”

“…Although analogous studies of BCR repertoires from RNA-seq are limited by insufficient resolution to detect phenomena such as somatic hypermutation and class switching, it is possible to assess BCR clonality, diversity, and recombination patterns from RNA-seq (36, 37). Although EBV infection has been associated with decreased TCR diversity in some EBV-positive cancers, reflecting a possible antigen-driven proliferative response (117), another study has tied EBV infection to increases in B-cell receptor diversity and abundance, likely due to increased infiltration of B lymphocytes (57). The abnormalities of TCR repertoires that are associated with T-cell neoplasms, as well as an incomplete understanding of CDR3-epitope relationships for EBV, preclude analysis of the functional characteristics of the T-cell response to EBV in PTCLs.…”

High pretreatment plasma Epstein‐Barr virus (EBV) DNA level is a poor prognostic marker in HIV‐associated, EBV‐negative diffuse large B‐cell lymphoma in Malawi

“…Interestingly, a recent study demonstrated that the presence of EBV‐positive, non‐neoplastic bystander cells are associated with increased IPI score and decreased OS in patients with tumor EBV‐negative DLBCL, though HIV status was not reported . Additionally, studies from The Cancer Genome Atlas found the tumor immune microenvironment was altered significantly by EBV‐positive bystander cell infiltration in HIV‐negative solid tumors, suggesting that EBV reactivation in nontumor cells may influence tumor biology.…”

Using RNA Sequencing to Characterize the Tumor Microenvironment

“…Expression of viral and human endogenous retroviral (hERV) RNA can drive immunological phenotypes in cancer [6,42]. We have developed tools for quantification of vertebrate viral and human endogenous retroviral (hERV) transcripts from RNA-seq data.…”

“…We have developed tools for quantification of vertebrate viral and human endogenous retroviral (hERV) transcripts from RNA-seq data. The first of these tools is VirDetect, which specifically detects viruses from RNA sequencing [42]. Reads are aligned to the human genome and reads that do not align to the human genome are then aligned to the masked viral genomes.…”