Unravelling the heterogenous molecular landscape of pediatric post-transplant lymphoproliferative disorders

Abstract The genetic landscape of post-transplant lymphoproliferative disorders (PTLD) in pediatric population has not been fully elucidated. This absence of information raises the question whether therapeutic strategies should be the same as for their counterparts in immunocompetent (IC) patients. The aim of this study was to characterize genetically and immunophenotypically pediatric monomorphic PTLD. Thirty-nine monomorphic PTLD ≤19 years-old (mean 10y, gender 25 male/14 female) were recruited and analyzed for germinal center markers, IRF4 and EBER expression. Presence of MYC, PAX5, IRF4, BCL2, BCL6 and 11q alterations was investigated by FISH. Additional molecular studies included clonality, copy number (CN) arrays, cell of origin-COO (Nanostring) and mutational analyses (Custom 167 lymphoma related genes panel, SureSelectXT, Agilent). Twenty-nine patients received solid organ transplantation and eight were hematopoietic stem cell transplant recipients. The mean time from transplant to PTLD diagnosis was 34 months (range 2-170) and the estimated 5-year overall survival (5y-OS) rate was 67%. Patients that received a solid organ had a better prognosis than hematopoietic stem cell transplant recipients (5y-OS 83% vs. 38%, p=0.03). Thirty-three cases were classified as diffuse large B-cell lymphoma (DLBCL) and six as Burkitt lymphoma (BL). Thirty-two cases had extranodal localization, 21 of which in the gastrointestinal tract. Among the DLBCL, 24/28 cases had an ABC/non-GC COO phenotype and the six BL were GCB. EBER was positive in 33/37 cases. Five out of six BL and one DLBCL had MYC rearrangements, while no 11q alterations or other rearrangements were observed. Ten out of the 23 pediatric monomorphic PTLD studied displayed CN alterations (mean 1.6 alt/case; range 0-12). Comparative analyses showed that pediatric PTLD had lower genetic complexity than BL (Scholtysik, 2010) and DLBCL (Ramis-Zaldivar, 2020) in IC patients and adult-PTLD (Ferreiro, 2016; Rinaldi, 2010) and lacked characteristic CN alterations of those groups. Regarding the mutational profile, all 6 PTLD-BL carried MYC mutations in addition to ID3 (4 cases), ARID1A (2 cases) or CCND3 (1 case) and a higher mutational burden than PTLD-DLBCL (12.3 vs 6.2, p=0.01). PTLD-DLBCL showed a very heterogeneous profile characterized by a lower number of mutations than their counterparts in IC patients (2.4 vs 6.5, p=0.01). Pathway enrichment analysis revealed that epigenetic modifiers and NOTCH pathway (4 cases each) were the most recurrently affected. Two out of 20 cases were classified as N1 according to LymphGen (Wright, 2020) algorithm while the rest remained undetermined. The mutational profile of pediatric PTLD-BL is similar to that observed in IC patients whereas PTLD-DLBCL are less complex than their counterpart in IC children and present a very heterogeneous mutational landscape with enrichment in NOTCH pathway mutations. Citation Format: Julia Salmeron, Natalia Castrejón-de-Anta, Pilar Guerra-Garcia, Joan Enric Ramis-Zaldivar, Mónica López-Guerra, Dolors Colomer, Francisco Diaz-Crespo, Marta Garrido, Javier Menarguez, Maria del Mar Andrés, Eugenia Garcia-Fernandez, Margarita Llavador, Noelia Garcia, Blanca Gonzalez-Farré, Idoia Martin-Guerrero, Carmen Garrido, Itziar Astigarraga, Alba Fernández, Jaime Verdú-Amorós, Soledad González-Muñíz, Berta Gonzalez, Verónica Celis, Elias Campo, Olga Balagué, Itziar Salaverria. Unravelling the heterogenous molecular landscape of pediatric post-transplant lymphoproliferative disorders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2502.