Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy...

Area of Science:

• Virology
• Genomics
• Oncology

Background:

• Epstein-Barr virus (EBV) is a significant carcinogen causing global morbidity and mortality.
• EBV-specific lymphocyte therapies show promise but their efficacy may be affected by EBV genome variations.
• The impact of EBV genome diversity on therapeutic strategies is largely unexplored.

Purpose of the Study:

• To investigate the geographic and cancer-specific variation in Epstein-Barr virus (EBV) genomes.
• To identify EBV variants associated with specific cancer types, particularly natural killer (NK)/T-cell lymphoma (NKTCL).
• To assess the implications of EBV genome variation for adaptive immune responses and vaccine development.

Main Methods:

• Sequencing of 217 EBV genomes from hematologic malignancies and analysis alongside 1307 public EBV genomes.
• Comparative genomic analysis across diverse geographic regions and disease types.
• Identification and association analysis of EBV variants with cancer risk and immunogenic epitopes.

Main Results:

• EBV genome variants are more strongly associated with geographic origin than cancer histology.
• Multiple NKTCL-specific EBV variants were identified, increasing cancer risk significantly (7.8- to 21.9-fold) after controlling for geography.
• Frequent EBV genome variations were observed affecting peptide binding to major histocompatibility complex (MHC) alleles and vaccine target proteins.

Conclusions:

• Geographic variation in EBV genomes is a critical factor influencing therapeutic strategies.
• Understanding global EBV diversity is essential for developing effective and equitable EBV-targeted cancer therapies and vaccines.
• EBV genome variations impact immune evasion and vaccine target efficacy, necessitating tailored approaches.