Mutations in latent membrane protein 1 of Epstein-Barr virus are associated with increased risk of posttransplant lymphoproliferative disorder in children

Olivia M Martinez¹, Sheri M Krams², Mark A Robien³, Mary G Lapasaran⁴, Matthew P Arvedson⁴, Andrea Reitsma⁴, Yarl Balachandran⁴, Aleishia Harris-Arnold², Kenneth Weinberg⁵, Scott D Boyd⁶, Brian Armstrong⁷, Amber Trickey⁴, Clare J Twist⁸, Dita Gratzinger⁶, Brent Tan⁶, Merideth Brown³, Clifford Chin⁹, Dev M Desai¹⁰, Thomas M Fishbein¹¹, George V Mazariegos¹², Akin Tekin¹³, Robert S Venick¹⁴, Daniel Bernstein⁵, Carlos O Esquivel⁴

Affiliations

¹ Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA; Stanford Immunology, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address: omm@stanford.edu.
² Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA; Stanford Immunology, Stanford University School of Medicine, Palo Alto, California, USA.
³ National Institute of Allergy and Infectious Disease, Rockville, Maryland, USA.
⁴ Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA.
⁵ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁷ Rho, Durham, North Carolina, USA.
⁸ Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
⁹ Department of Pediatrics and Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁰ University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹¹ Departments of Surgery and Pediatrics, MedStar Georgetown University Hospital, Georgetown, Washington, DC, USA.
¹² University of Pittsburgh Medical Center, Children's Hospital Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹³ Miller School of Medicine, University of Medicine, Florida, USA.
¹⁴ David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

PMID: 36796762
PMCID: PMC10159954
DOI: 10.1016/j.ajt.2023.02.014

Mutations in latent membrane protein 1 of Epstein-Barr virus are associated with increased risk of posttransplant lymphoproliferative disorder in children

Olivia M Martinez et al. Am J Transplant. 2023 May.

. 2023 May;23(5):611-618.

doi: 10.1016/j.ajt.2023.02.014. Epub 2023 Feb 15.

Authors

Affiliations

¹ Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA; Stanford Immunology, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address: omm@stanford.edu.
² Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA; Stanford Immunology, Stanford University School of Medicine, Palo Alto, California, USA.
³ National Institute of Allergy and Infectious Disease, Rockville, Maryland, USA.
⁴ Department of Surgery, Stanford University School of Medicine, Palo Alto, California, USA.
⁵ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁷ Rho, Durham, North Carolina, USA.
⁸ Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
⁹ Department of Pediatrics and Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio, USA.
¹⁰ University of Texas Southwestern Medical Center, Dallas, Texas, USA.
¹¹ Departments of Surgery and Pediatrics, MedStar Georgetown University Hospital, Georgetown, Washington, DC, USA.
¹² University of Pittsburgh Medical Center, Children's Hospital Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹³ Miller School of Medicine, University of Medicine, Florida, USA.
¹⁴ David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.

PMID: 36796762
PMCID: PMC10159954
DOI: 10.1016/j.ajt.2023.02.014

Abstract

Epstein-Barr virus (EBV)-positive posttransplant lymphoproliferative disorder (PTLD) results in significant morbidity and mortality in pediatric transplant recipients. Identifying individuals at an increased risk of EBV-positive PTLD could influence clinical management of immunosuppression and other therapies, improving posttransplant outcomes. A 7-center prospective, observational clinical trial of 872 pediatric transplant recipients evaluated the presence of mutations at positions 212 and 366 of EBV latent membrane protein 1 (LMP1) as an indicator of risk of EBV-positive PTLD (clinical trials: NCT02182986). DNA was isolated from peripheral blood of EBV-positive PTLD case patients and matched controls (1:2 nested case:control), and the cytoplasmic tail of LMP1 was sequenced. Thirty-four participants reached the primary endpoint of biopsy-proven EBV-positive PTLD. DNA was sequenced from 32 PTLD case patients and 62 matched controls. Both LMP1 mutations were present in 31 of 32 PTLD cases (96.9%) and in 45 of 62 matched controls (72.6%) (P = .005; OR = 11.7; 95% confidence interval, 1.5, 92.6). The presence of both G212S and S366T carries a nearly 12-fold increased risk of development of EBV-positive PTLD. Conversely, transplant recipients without both LMP1 mutations carry a very low risk of PTLD. Analysis of mutations at positions 212 and 366 of LMP1 can be informative in stratifying patients for risk of EBV-positive PTLD.

Keywords: B cell lymphoma; EBV; LMP1; PTLD; pediatric transplantation.

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Conflict of interest statement

DISCLOSURES

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Figure 1:. Participants, Groups and PTLD cases.**
A total of 944 participants were enrolled either pre-transplant (Group 1) or post-transplant (Group 2). 72 participants did not receive a transplant. Groups included participants who were EBV+ at transplant (Groups 1A and 2A) or were EBV− at transplant (Groups 1B and 2B). EBV status at transplant was unknown in 61 participants. A total of 34 participants reached the study endpoint of EBV+ PTLD.

**Figure 2:. Frequency of distinct amino acid combinations at position 212 and position 366 of the cytoplasmic tail of EBV LMP1.**
Controls (orange) and EBV+ PTLD cases (blue).

See this image and copyright information in PMC

References

1. Fishman JA. Infection in Organ Transplantation. Am J Transplant. Apr 2017;17(4):856–879. doi:10.1111/ajt.14208 - DOI - PubMed
1. Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation. Oct 15 2005;80(2 Suppl):S254–64. doi:10.1097/01.tp.0000186382.81130.ba - DOI - PubMed
1. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. May 19 2016;127(20):2375–90. doi:10.1182/blood-2016-01-643569 - DOI - PMC - PubMed
1. Dierickx D, Habermann TM. Post-Transplantation Lymphoproliferative Disorders in Adults. N Engl J Med. Feb 8 2018;378(6):549–562. doi:10.1056/NEJMra1702693 - DOI - PubMed
1. Robinson CH, Coughlin CC, Chanchlani R, Dharnidharka VR. Post-transplant malignancies in pediatric organ transplant recipients. Pediatr Transplant. Feb 2021;25(1):e13884. doi:10.1111/petr.13884 - DOI - PubMed

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Mutations in latent membrane protein 1 of Epstein-Barr virus are associated with increased risk of posttransplant lymphoproliferative disorder in children

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Mutations in latent membrane protein 1 of Epstein-Barr virus are associated with increased risk of posttransplant lymphoproliferative disorder in children

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Conflict of interest statement

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