TY - JOUR
T1 - Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses
AU - Briercheck, Edward L.
AU - Ravishankar, Shashidhar
AU - Ahmed, Elshafa Hassan
AU - Alvarado, César Camilo Carías
AU - Menéndez, Juan Carlos Barrios
AU - Silva, Oscar
AU - Solórzano-Ortiz, Elizabeth
AU - Tala, Marcos Mauricio Siliézar
AU - Stevenson, Philip
AU - Xu, Yuexin
AU - Wohns, Anthony Wilder
AU - Enriquez-Vera, Daniel
AU - Barrionuevo, Carlos
AU - Yu, Shan Chi
AU - Freud, Aharon G.
AU - Oakes, Christopher
AU - Weigel, Christoph
AU - Weinstock, David M.
AU - Klimaszewski, Haley L.
AU - Ngankeu, Apollinaire
AU - Mutalima, Nora
AU - Samayoa-Reyes, Gabriela
AU - Newton, Robert
AU - Rochford, Rosemary
AU - Valvert, Fabiola
AU - Natkunam, Yasodha
AU - Shustov, Andrei
AU - Baiocchi, Robert A.
AU - Warren, Edus H.
N1 - Publisher Copyright:
© 2024 by The American Society of Hematology.
PY - 2024/7/23
Y1 - 2024/7/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85199554539&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2023012461
DO - 10.1182/bloodadvances.2023012461
M3 - Article
C2 - 38815238
AN - SCOPUS:85199554539
SN - 2473-9529
VL - 8
SP - 3731
EP - 3744
JO - Blood Advances
JF - Blood Advances
IS - 14
ER -