Division of Pediatric Hematology-Oncology, Department of Pediatrics, Mackay Memorial Hospital and Mackay Medical College, Taipei, Taiwan.
Division of Hematology-Oncology, Department of Pediatrics, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.
Pediatr Blood Cancer. 2019 Jan;66(1):e27496. doi: 10.1002/pbc.27496. Epub 2018 Oct 2.
The leukemogenesis of T-cell acute lymphoblastic leukemia (T-ALL) involves multistep processes of genetic alterations. We aimed to determine the genetic alterations including common fusion transcripts, overexpression of T-cell transcription factor oncogenes, and deletion or mutation of targeted genes in pediatric T-ALL in Taiwan as well as their impact on outcomes in those treated with the Taiwan Pediatric Oncology Group-ALL-2002 protocol.
Between 1995 and 2015, bone marrow samples obtained from 102 children aged <18 years consecutively diagnosed with T-ALL were examined. Thirty-two genetic alterations were examined by reverse transcription polymerase chain reaction (PCR) assays-PCR-based assays-followed by direct sequencing, real time quantitative PCR with TaqMan assays, or multiplex ligase probe amplification.
TAL1 overexpression, CDKN2A/2B deletions, and NOTCH1 mutation were the most frequent aberrations while none had NF1, SUZ12 deletion, JAK1 or JAK2 mutations, or NUP214-ABL1 fusion in our cohort. The most frequent cooperating occurrence of genetic alterations included CDKN2A/2B and MTAP, MTAP and CDKN2B, LEF1 and PTPN2, and HOX11L2 and PHF6 mutation/deletion. NOTCH1 mutations conferred a favorable overall survival, whereas SIL-TAL1 fusion, TAL overexpression, LEF1 deletion, and PHF6 deletion/mutation were associated with an inferior outcome. By multivariate analysis, PHF6 mutation/deletion was the only independent predictor for inferior overall survival.
The present study showed that the frequencies of genetic alterations in Taiwanese children with T-ALL differed considerably from those reported in Western countries. PHF6 mutation/deletion was an independently adverse predictor.
T 细胞急性淋巴细胞白血病（T-ALL）的白血病发生涉及遗传改变的多步过程。我们旨在确定包括常见融合转录本、T 细胞转录因子癌基因的过表达以及靶向基因缺失或突变在内的遗传改变，以及它们对接受台湾儿科肿瘤组 ALL-2002 方案治疗的患儿的结局的影响。
1995 年至 2015 年，连续诊断为 T-ALL 的 102 名<18 岁的儿童的骨髓样本进行了检查。通过逆转录聚合酶链反应（PCR）检测 32 种遗传改变-基于 PCR 的检测方法-随后直接测序、实时定量 PCR 与 TaqMan 检测或多重连接探针扩增。
TAL1 过表达、CDKN2A/2B 缺失和 NOTCH1 突变是最常见的异常，而我们的队列中没有 NF1、SUZ12 缺失、JAK1 或 JAK2 突变或 NUP214-ABL1 融合。最常见的遗传改变共同发生包括 CDKN2A/2B 和 MTAP、MTAP 和 CDKN2B、LEF1 和 PTPN2，以及 HOX11L2 和 PHF6 突变/缺失。NOTCH1 突变与总生存有利相关，而 SIL-TAL1 融合、TAL 过表达、LEF1 缺失和 PHF6 缺失/突变与较差的结局相关。通过多变量分析，PHF6 突变/缺失是总生存不良的唯一独立预测因子。
本研究表明，台湾儿童 T-ALL 的遗传改变频率与西方国家报道的差异很大。PHF6 突变/缺失是独立的不良预后预测因子。
