Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
Department of Hematology-Oncology, Mackay Children's Hospital and Mackay Medical College, Taipei, Taiwan.
Pediatr Blood Cancer. 2021 Apr;68(4):e28899. doi: 10.1002/pbc.28899. Epub 2021 Feb 1.
IKZF1deletion is an unfavorable factor in Philadelphia negative (Ph -) B-cell acute lymphoblastic leukemia. However, the effects of IKZF1 deletions co-existing genetic alterations in Ph (-) ALL have not been extensively studied.
Bone marrow samples from 368 children with Ph (-) ALL were analyzed by using multiplex ligation-dependent probe amplification kit for detection of gene deletions and Sanger sequencing for mutational analysis of RAS pathway genes. The outcome was analyzed on 215 patients treated with Taiwan Pediatric Oncology Group-ALL-2002 protocol.
IKZF1 deletions were present in 12.8% and IKZF1 in 6.3% of patients. Mutations of RAS pathway genes were detected in 25.0% of IKZF1-deleted patients. The 10-year event-free survival (EFS) of IKZF1-undeleted patients was significantly better compared with IKZF1-deleted patients (80.0% vs. 47.8%, p = 0.001). Compared with outcome of patients harboring IKZF1 deletion alone, no difference in EFS was observed in patients with IKZF1 , whereas three patients carried both IKZF1 and ERG deletions had a superior 10-year EFS (100%). The 10-year EFS of patients with any gene mutation of RAS pathway was worse than that of patients with wild-type genes (79.1% vs. 61.6%, p = 0.033). In multivariate analysis, RAS pathway mutations and IKZF1 deletion were independent predictors of inferior EFS. Co-existence of IKZF1 deletion with RAS pathway mutations had a worst 10-year EFS (11.1 ± 10.5%) and 10-year OS (53.3 ± 17.6%).
Our results showed that RAS pathway mutation is an added-value biomarker in pediatric IKZF1-deleted Ph (-) ALL patients.
IKZF1 缺失是费城染色体阴性（Ph-）B 细胞急性淋巴细胞白血病的不利因素。然而，Ph-ALL 中 IKZF1 缺失合并其他遗传改变的影响尚未得到广泛研究。
采用多重连接依赖探针扩增试剂盒检测基因缺失，Sanger 测序分析 RAS 通路基因突变，对 368 例 Ph-ALL 患儿骨髓样本进行分析。采用台湾儿科肿瘤组 ALL-2002 方案治疗的 215 例患者进行了结局分析。
IKZF1 缺失见于 12.8%的患者，IKZF1 缺失见于 6.3%的患者。IKZF1 缺失患者中检测到 RAS 通路基因突变 25.0%。IKZF1 未缺失患者的 10 年无事件生存（EFS）明显优于 IKZF1 缺失患者（80.0%vs.47.8%，p=0.001）。与仅携带 IKZF1 缺失的患者相比，IKZF1 缺失的患者 EFS 无差异，而 3 例患者同时携带 IKZF1 和 ERG 缺失，10 年 EFS 较高（100%）。RAS 通路基因任何基因突变患者的 10 年 EFS 均较野生型基因患者差（79.1%vs.61.6%，p=0.033）。多因素分析显示，RAS 通路基因突变和 IKZF1 缺失是 EFS 不良的独立预测因素。IKZF1 缺失合并 RAS 通路基因突变患者的 10 年 EFS 最差（11.1±10.5%），10 年 OS 最差（53.3±17.6%）。
我们的结果表明，RAS 通路突变是儿童 IKZF1 缺失型 Ph-ALL 患者的附加价值生物标志物。
