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Decoding the molecular heterogeneity of pediatric monomorphic post–solid organ transplant lymphoproliferative disorders

2023; Elsevier BV; Volume: 142; Issue: 5 Linguagem: Inglês

10.1182/blood.2022019543

1528-0020

Julia Salmerón‐Villalobos, Natalia Castrejón de Anta, Pilar Guerra‐García, Joan E. Ramis-Zaldivar, Mònica López‐Guerra, Sara Mato, Dolors Colomer, Francisco Díaz‐Crespo, Javier Menárguez, Marta Garrido‐Pontnou, Mara Andrés, Eugenia García‐Fernández, Margarita Llavador, Gerard Frigola, Noelia García Barrio, Blanca González‐Farré, Idoia Martín‐Guerrero, Carmen Garrido Colino, Itziar Astigarraga, Alba S. García Fernández, Jaime Verdú‐Amorós, Soledad González-Muñíz, Berta González, Verónica Celis, Elı́as Campo, Olga Balagué, Itziar Salaverría,

Chronic Lymphocytic Leukemia Research

Abstract Posttransplant lymphoproliferative disorders (PTLDs) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLDs) has not been elucidated, and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 cases of pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCLs), mostly classified as activated B cell, and 7 cases of Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. Overall, PTLD-BL carried mutations in MYC, ID3, DDX3X, ARID1A, or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL, and lesser CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of the Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with a worse outcome. All 7 patients with PTLD-BL were alive after treatment with pediatric B-cell non-Hodgkin lymphoma protocols, whereas 54% of patients with DLBCL were cured with immunosuppression reduction, rituximab, and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low-intensity treatment, and the shared pathogenesis between PTLD-BL and EBV-positive IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.