Liu Shu-Guang, Gao Chao, Zhang Rui-Dong, Zhao Xiao-Xi, Cui Lei, Li Wei-Jing, Chen Zhen-Ping, Yue Zhi-Xia, Zhang Yuan-Yuan, Wu Min-Yuan, Wang Jian-Xiang, Li Zhi-Gang, Zheng Hu-Yong
Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 30020, China.
Oncotarget. 2017 Jun 6;8(23):37761-37772. doi: 10.18632/oncotarget.17781.
High-dose methotrexate (HDMTX) plays an important role in the treatment of acute lymphoblastic leukemia (ALL) although there is great inter-patient variability in the efficacy and toxicity of MTX. The relationship between polymorphisms in genes encoding MTX transporters and MTX response is controversial. In the present study, 322 Chinese children with standard- and intermediate-risk ALL were genotyped for 12 polymorphisms. SLCO1B1 rs10841753 showed a significant association with plasma MTX levels at 48 h (P = 0.017). Patients who had the ABCB1 rs1128503 C allele had longer duration of hospitalization than did those with the TT genotype (P = 0.006). No association was found between oral mucositis and any polymorphism. Long-term outcome was worse in patients with the SLCO1B1 rs4149056 CC genotype than in patients with TT or TC (5-year event-free survival [EFS] 33.3 ± 19.2% vs. 90.5 ± 1.7%, P < 0.001), and was worse in patients with the SCL19A1 rs2838958 AA genotype than in patients with AG or GG (5-year EFS 78.5 ± 4.6% vs. 92.2 ± 1.8%, P = 0.008). Multiple Cox regression analyses revealed associations of minimal residual disease (MRD) at day 33 (hazard ratio 3.458; P = 0.002), MRD at day 78 (hazard ratio 6.330; P = 0.001), SLCO1B1 rs4149056 (hazard ratio 12.242; P < 0.001), and SCL19A1 rs2838958 (hazard ratio 2.324; P = 0.019) with EFS. Our findings show that polymorphisms in genes encoding MTX transporters substantially influence the kinetics and response to HDMTX therapy in childhood ALL.
大剂量甲氨蝶呤（HDMTX）在急性淋巴细胞白血病（ALL）的治疗中发挥着重要作用，尽管患者间甲氨蝶呤的疗效和毒性存在很大差异。编码甲氨蝶呤转运蛋白的基因多态性与甲氨蝶呤反应之间的关系存在争议。在本研究中，对322例中国标准风险和中度风险ALL儿童进行了12种多态性的基因分型。SLCO1B1 rs10841753与48小时时的血浆甲氨蝶呤水平显著相关（P = 0.017）。携带ABCB1 rs1128503 C等位基因的患者住院时间比携带TT基因型的患者更长（P = 0.006）。未发现口腔黏膜炎与任何多态性之间存在关联。SLCO1B1 rs4149056 CC基因型患者的长期预后比TT或TC基因型患者更差（5年无事件生存率[EFS] 33.3±19.2%对90.5±1.7%，P < 0.001），SCL19A1 rs2838958 AA基因型患者的长期预后比AG或GG基因型患者更差（5年EFS 78.5±4.6%对92.2±1.8%，P = 0.008）。多项Cox回归分析显示，第33天的微小残留病（MRD）（风险比3.458；P = 0.002）、第78天的MRD（风险比6.330；P = 0.001）、SLCO1B1 rs4149056（风险比12.242；P < 0.001）和SCL19A1 rs2838958（风险比2.324；P = 0.019）与EFS相关。我们的研究结果表明，编码甲氨蝶呤转运蛋白的基因多态性在很大程度上影响儿童ALL患者HDMTX治疗的动力学和反应。
