基于下一代测序的急性髓性白血病患儿基因组分析。
NEXT-GENERATION SEQUENCING-BASED GENOMIC PROFILING OF CHILDREN WITH ACUTE MYELOID LEUKEMIA.
发表日期：2023 Apr 21
作者：
Szilvia Krizsán, Borbála Péterffy, Bálint Egyed, Tibor Nagy, Endre Sebestyén, Lajos László Hegyi, Zsuzsanna Jakab, Dániel J Erdélyi, Judit Müller, György Péter, Krisztina Csanádi, Krisztián Kállay, Gergely Kriván, Gábor Barna, Gábor Bedics, Irén Haltrich, Gábor Ottóffy, Katalin Csernus, Ágnes Vojcek, Lilla Györgyi Tiszlavicz, Krisztina Mita Gábor, Ágnes Kelemen, Péter Hauser, Zsuzsanna Gaál, István Szegedi, Anikó Ujfalusi, Béla Kajtár, Csongor Kiss, András Matolcsy, Botond Tímár, Gábor Kovács, Donát Alpár, Csaba Bödör
来源：
Experimental Hematology & Oncology
摘要：
小儿急性髓系白血病（AML）是儿童白血病死亡的主要原因之一，但仅有有限的研究调查了该疾病的分子景观。在这里，我们对于按AML BFM方案治疗的一个多中心真实患者队列中的75例小儿AML患者的细胞遗传学和分子特征进行了综合分析。对于54个基因的定向下一代测序（NGS）显示出有17个基因在5%以上的患者中经常发生突变。与以往的研究相比，突变分布的明显不同包括在更高频率上检测到BCORL1、CUX1、KDM6A、PHF6和STAG2 的突变，而KIT、NRAS和KRAS的突变则较少。我们的研究发现了在BCORL1基因中新常见的诊断性突变在9%的患者中被发现。肿瘤抑制基因（PHF6、TP53、WT1）的突变被发现与诱导失败和短期无事件生存相关，表明这些改变在抵抗治疗和疾病进展中扮演着重要角色。在诊断和复发的突变构成比较中发现复发时肿瘤抑制基因（44.4%）和转录因子（55.6%）突变的富集。我们的研究结果进一步阐明了儿童AML的异质性，并确定了以前未被重视的变化，从而可能会导致改善对小儿AML的分子特征和风险分层。版权所有 © 2023. Elsevier Inc. 出版。
Pediatric acute myeloid leukemia (AML) represents a major cause of childhood leukemic mortality with only a limited number of studies investigating the molecular landscape of the disease. Here, we present an integrative analysis of cytogenetic and molecular profiles of 75 patients with pediatric AML from a multicentric, real-world patient cohort treated according to AML BFM protocols. Targeted next-generation sequencing (NGS) of 54 genes revealed 17 genes that were recurrently mutated in more than 5% of patients. Considerable differences were observed in the mutational profiles compared to previous studies as BCORL1, CUX1, KDM6A, PHF6 and STAG2 mutations were detected at a higher frequency than previously reported, whereas KIT, NRAS, and KRAS were less frequently mutated. Our study identified novel recurrent mutations at diagnosis in BCORL1 gene in 9% of the patients. Tumor suppressor gene (PHF6, TP53, WT1) mutations were found to be associated with induction failure and shorter event-free survival suggesting important roles of these alterations in resistance to therapy and disease progression. Comparison of the mutational landscape at diagnosis and relapse revealed an enrichment of mutations in tumor suppressor genes (16.2% vs. 44.4%) and transcription factors (35.1 vs. 55.6%) at relapse. Our findings shed further light on the heterogeneity of pediatric AML and identified previously unappreciated alterations that may lead to improved molecular characterization and risk stratification of pediatric AML.Copyright © 2023. Published by Elsevier Inc.