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

Edward L Briercheck; Shashidhar Ravishankar; Elshafa Hassan Ahmed; César Camilo Carías Alvarado; Juan Carlos Barrios Menéndez; Oscar Silva; Elizabeth Solórzano-Ortiz; Marcos Mauricio Siliézar Tala; Philip Stevenson; Yuexin Xu; Anthony Wilder Wohns; Daniel Enriquez-Vera; Carlos Barrionuevo; Shan-Chi Yu; Aharon G Freud; Christopher Oakes; Christoph Weigel; David M Weinstock; Haley L Klimaszewski; Apollinaire Ngankeu; Nora Mutalima; Gabriela Samayoa-Reyes; Robert Newton; Rosemary Rochford; Fabiola Valvert; Yasodha Natkunam; Andrei Shustov; Robert A Baiocchi; Edus H Warren

doi:10.1182/bloodadvances.2023012461

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

Edward L Briercheck, Shashidhar Ravishankar, Elshafa Hassan Ahmed, César Camilo Carías Alvarado, Juan Carlos Barrios Menéndez, Oscar Silva, Elizabeth Solórzano-Ortiz, Marcos Mauricio Siliézar Tala, Philip Stevenson, Yuexin Xu, Anthony Wilder Wohns, Daniel Enriquez-Vera, Carlos Barrionuevo, Shan-Chi Yu, Aharon G Freud, Christopher Oakes, Christoph Weigel, David M Weinstock, Haley L Klimaszewski, Apollinaire NgankeuNora Mutalima, Gabriela Samayoa-Reyes, Robert Newton, Rosemary Rochford, Fabiola Valvert, Yasodha Natkunam, Andrei Shustov, Robert A Baiocchi, Edus H Warren

Health Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	3731-3744
Number of pages	14
Journal	Blood Advances
Volume	8
Issue number	14
DOIs	https://doi.org/10.1182/bloodadvances.2023012461
Publication status	Published - 12 Jul 2024

Bibliographical note

Keywords

Humans
Herpesvirus 4, Human/genetics
Epstein-Barr Virus Infections/immunology
Genetic Variation
Genome, Viral
Immunotherapy

Access to Document

10.1182/bloodadvances.2023012461Licence: CC BY-NC-ND

Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses
© 2024 by The American Society of Hematology.
Final published version, 3.49 MBLicence: CC BY-NC-ND

Cite this

Briercheck, E. L., Ravishankar, S., Ahmed, E. H., Carías Alvarado, C. C., Barrios Menéndez, J. C., Silva, O., Solórzano-Ortiz, E., Siliézar Tala, M. M., Stevenson, P., Xu, Y., Wohns, A. W., Enriquez-Vera, D., Barrionuevo, C., Yu, S.-C., Freud, A. G., Oakes, C., Weigel, C., Weinstock, D. M., Klimaszewski, H. L., ... Warren, E. H. (2024). Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses. Blood Advances, 8(14), 3731-3744. https://doi.org/10.1182/bloodadvances.2023012461

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title = "Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses",

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.",

keywords = "Humans, Herpesvirus 4, Human/genetics, Epstein-Barr Virus Infections/immunology, Genetic Variation, Genome, Viral, Immunotherapy",

author = "Briercheck, {Edward L} and Shashidhar Ravishankar and Ahmed, {Elshafa Hassan} and {Car{\'i}as Alvarado}, {C{\'e}sar Camilo} and {Barrios Men{\'e}ndez}, {Juan Carlos} and Oscar Silva and Elizabeth Sol{\'o}rzano-Ortiz and {Sili{\'e}zar Tala}, {Marcos Mauricio} and Philip Stevenson and Yuexin Xu and Wohns, {Anthony Wilder} and Daniel Enriquez-Vera and Carlos Barrionuevo and Shan-Chi Yu and Freud, {Aharon G} and Christopher Oakes and Christoph Weigel and Weinstock, {David M} and Klimaszewski, {Haley L} and Apollinaire Ngankeu and Nora Mutalima and Gabriela Samayoa-Reyes and Robert Newton and Rosemary Rochford and Fabiola Valvert and Yasodha Natkunam and Andrei Shustov and Baiocchi, {Robert A} and Warren, {Edus H}",

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Briercheck, EL, Ravishankar, S, Ahmed, EH, Carías Alvarado, CC, Barrios Menéndez, JC, Silva, O, Solórzano-Ortiz, E, Siliézar Tala, MM, Stevenson, P, Xu, Y, Wohns, AW, Enriquez-Vera, D, Barrionuevo, C, Yu, S-C, Freud, AG, Oakes, C, Weigel, C, Weinstock, DM, Klimaszewski, HL, Ngankeu, A, Mutalima, N, Samayoa-Reyes, G, Newton, R, Rochford, R, Valvert, F, Natkunam, Y, Shustov, A, Baiocchi, RA & Warren, EH 2024, 'Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses', Blood Advances, vol. 8, no. 14, pp. 3731-3744. https://doi.org/10.1182/bloodadvances.2023012461

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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 - Carías Alvarado, César Camilo

AU - Barrios Menéndez, Juan Carlos

AU - Silva, Oscar

AU - Solórzano-Ortiz, Elizabeth

AU - Siliézar Tala, Marcos Mauricio

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

PY - 2024/7/12

Y1 - 2024/7/12

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.

KW - Humans

KW - Herpesvirus 4, Human/genetics

KW - Epstein-Barr Virus Infections/immunology

KW - Genetic Variation

KW - Genome, Viral

KW - Immunotherapy

U2 - 10.1182/bloodadvances.2023012461

DO - 10.1182/bloodadvances.2023012461

M3 - Article

C2 - 38815238

SN - 2473-9529

VL - 8

SP - 3731

EP - 3744

JO - Blood Advances

JF - Blood Advances

IS - 14

ER -