解读儿童器官移植后单形性固体器官淋巴增殖性疾病的分子异质性。
Decoding the molecular heterogeneity of pediatric monomorphic post-solid organ transplant lymphoproliferative disorders.
发表日期：2023 Apr 13
作者：
Julia Salmerón-Villalobos, Natalia Castrejon-de-Anta, Pilar Guerra-Garcia, Joan Enric Ramis-Zaldivar, Mònica López-Guerra, Sara Mato, Dolors Colomer, Francisco Javier Diaz Crespo, Javier Menarguez, Marta Garrido-Pontnou, Mara Andres, Eugenia Garcia-Fernandez, Margarita Llavador, Gerard Frigola, Noelia Garcia, Blanca Gonzalez-Farre, Idoia Martin-Guerrero, Carmen Garrido-Colino, Itziar Astigarraga, Alba Fernandez, Jaime Verdu-Amorós, Soledad Gonzalez Muñiz, Berta González-Martínez, Verónica Celis, Elías Campo, Olga Balagué, Itziar Salaverria
来源：
BLOOD
摘要：
移植后淋巴增殖性疾病（PTLD）代表着广泛的淋巴细胞增殖，常常与EB病毒感染相关。儿童单形PTLD（mPTLD）的分子特征尚未阐明，也不知道它们是否与成人和免疫能力（IMC）儿童患者的对应物具有相似的基因特征。在本研究中，我们调查了31个器官移植后的儿童mPTLD，包括24个弥漫性大B细胞淋巴瘤（DLBCL），大多数被分类为活化B细胞，以及七个Burkitt淋巴瘤（BL），其中93％为EB病毒阳性。我们采用了综合的分子方法，包括荧光原位杂交、有针对性的基因测序和拷贝数（CN）数组。整体而言，PTLD-BL携带了MYC、ID3、DDX3X、ARID1A或CCND3的突变，类似于IMC-BL，比PTLD-DLBCL具有更高的突变负荷和比IMC-BL更少的CN改变。 PTLD-DLBCL表现出非常不均匀的基因组特征，突变和CN变化比IMC-DLBCL更少。在PTLD-DLBCL中，表观遗传修饰因子和Notch途径中的基因最经常突变（均为28％）。细胞周期和Notch途径的突变与更糟的结局相关。经过小儿B细胞非霍奇金淋巴瘤方案治疗后，七个PTLD-BL全部存活，而54％的DLBCL患者通过免疫抑制减少、利妥昔单抗和/或低剂量化疗治愈。这些发现凸显了儿童PTLD-DLBCL的低复杂性、其对低强度治疗的良好反应以及PTLD-BL和EBV + IMC-BL之间的共同发病机制。我们还建议新的潜在参数，这些参数可能有助于诊断和设计更好的治疗策略。版权所有©2023美国血液学会。
Post-transplant lymphoproliferative disorders (PTLD) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr Virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLD) 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 pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCL), mostly classified as activated B-cell, and seven 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 less 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 Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with worse outcome. All seven PTLD-BL were alive after treatment with pediatric B-cell Non-Hodgkin Lymphoma protocols, whereas 54% of DLBCL patients 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+ IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.Copyright © 2023 American Society of Hematology.