Integrating Epstein-Barr virus (EBV) status into diffuse large B cell lymphoma (DLBCL) genetics

Area of Science:

• Oncology
• Virology
• Genetics

Background:

• Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma, with approximately 5-15% of cases associated with Epstein-Barr virus (EBV).
• Existing molecular subtypes of DLBCL do not fully account for EBV-associated cases, highlighting a gap in current classification systems.

Purpose of the Study:

• To investigate the molecular characteristics and classification of EBV-positive DLBCL.
• To evaluate the utility of current in vitro models for studying EBV-positive DLBCL.

Main Methods:

• Reanalysis of whole-exome and RNA-sequencing data from 481 DLBCL tumors to identify EBV-positive cases.
• Analysis of EBV-positive cell lines and comparison with tumor data, including viral latency programs.

Main Results:

• Nineteen EBV-positive DLBCL cases were identified, enriched in the BN2 molecular subtype.
• EBV-positive BN2 tumors showed reduced frequencies of subtype-defining mutations, suggesting EBV oncogenes may substitute for cellular alterations.
• EBV-positive DLBCL is heterogeneous, exhibiting different viral latency patterns (I, II, and atypical III).
• The Val cell line harbors a laboratory strain of EBV and is not representative.
• Existing EBV-positive DLBCL cell lines model only non-BN2 subtypes and express an atypical viral latency III program.

Conclusions:

• EBV-positive DLBCL is not a monolithic entity and exhibits significant biological heterogeneity.
• EBV status influences DLBCL classification, potentially confounding genetic-based algorithms.
• Current in vitro models, including the Val cell line, inadequately represent the complexity and diversity of EBV-positive DLBCL.