Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses.
Journal
Blood advances
Journal Volume
8
Journal Issue
14
Start Page
3731
End Page
3744
ISSN
2473-9537
Date Issued
2024-07-23
Author(s)
Briercheck, Edward L
Ravishankar, Shashidhar
Ahmed, Elshafa Hassan
Carías Alvarado, César Camilo
Barrios Menéndez, Juan Carlos
Silva, Oscar
Solórzano-Ortiz, Elizabeth
Siliézar Tala, Marcos Mauricio
Stevenson, Philip
Xu, Yuexin
Wohns, Anthony Wilder
Enriquez-Vera, Daniel
Barrionuevo, Carlos
Freud, Aharon G
Oakes, Christopher
Weigel, Christoph
Weinstock, David M
Klimaszewski, Haley L
Ngankeu, Apollinaire
Mutalima, Nora
Samayoa-Reyes, Gabriela
Newton, Robert
Rochford, Rosemary
Valvert, Fabiola
Natkunam, Yasodha
Shustov, Andrei
Baiocchi, Robert A
Warren, Edus H
Abstract
Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies and causes significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1307 publicly available EBV genomes from cancer, nonmalignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included, to our knowledge, the first natural killer (NK)/T-cell lymphoma (NKTCL) EBV genomes reported outside of East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than to cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8-fold to 21.9-fold increased risk. We also observed frequent variations in EBV genomes that affected peptide sequences previously reported to bind common major histocompatibility complex alleles. Finally, we found several nonsynonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.
SDGs
Type
journal article