急性淋巴细胞白血病患儿MTHFR基因多态性与临床预后和甲氨蝶呤化疗毒性的相关性研究
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摘要
目的考察急性淋巴细胞白血病(ALL)患儿MTHFR rs1801131 A> C基因多态性对临床预后和甲氨蝶呤(MTX)化疗毒性的影响。方法收集134例ALL患儿的外周血,提取基因组DNA,用基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)技术分析MTHFR rs1801131 A> C基因型。结果 MTHFR rs1801131 CC基因型患儿的平均无事件生存间期(EFI)为26. 83个月,显著长于AC基因型患儿(15. 72个月,P <0. 05),CC基因型患儿的复发率(0)低于AA(9. 37%)和AC(12. 50%)基因型患儿,但差异无统计学意义。除了肝和电解质不良事件在CC基因型患儿中的发生率(33. 33%和16. 67%)高于AA(12. 50%和14. 58%)和AC(18. 75%和3. 13%)基因型患儿以外,其余不良事件在CC基因型患儿中的发生率低于AA和AC基因型患儿,3种基因型之间的MTX化疗毒性发生率差异无统计学意义。结论 MTHFR rs1801131 A> C基因多态性与ALL患儿临床预后显著相关,但与MTX化疗毒性无显著相关性。
Objective To investigate the association between methylenetetrahydrofolate reductase( MTHFR) rs1801131 A > C polymorphisms and clinical prognosis and toxicities of methotrexate( MTX) chemotherapy in children with acute lymphoblastic leukemia( ALL). Methods Peripheral blood samples were obtained from children with ALL( n = 134)to extract genome DNA. Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry( MALDI-TOF-MS) was used to detect the genotypes of MTHFR rs1801131 A > C polymorphisms. Results The average event free intervals( EFI) in children with MTHFR rs1801131 CC genotype( 26. 83 months) were significantly longer than those in AC genotype carriers( 15. 72 months,P < 0. 05). The relapse rate in patients with CC genotype( 0) was lower than those in AA( 9. 37%) and AC( 12. 50%) genotype carriers,but the differences were not statistically significant. The incidences of hepatic disorders and electrolyte disorders in children with CC genotype( 33. 33% and 16. 67%,respectively) were higher than those in AA( 12. 50% and 14. 58%) and AC( 18. 75% and 3. 13%) genotype carriers. The incidences of other adverse events in patients with CC genotype were lowerthan those in AA and AC genotype carriers. The differences in the incidences of MTX toxicities among three genotypes did not achieve statistical significance. Conclusion MTHFR rs1801131 A > C polymorphisms were significantly associated with clinical prognosis of ALL children. There were no significant associations between the investigated polymorphisms and toxicities of MTX.
Objective To investigate the association between methylenetetrahydrofolate reductase( MTHFR) rs1801131 A > C polymorphisms and clinical prognosis and toxicities of methotrexate( MTX) chemotherapy in children with acute lymphoblastic leukemia( ALL). Methods Peripheral blood samples were obtained from children with ALL( n = 134)to extract genome DNA. Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry( MALDI-TOF-MS) was used to detect the genotypes of MTHFR rs1801131 A > C polymorphisms. Results The average event free intervals( EFI) in children with MTHFR rs1801131 CC genotype( 26. 83 months) were significantly longer than those in AC genotype carriers( 15. 72 months,P < 0. 05). The relapse rate in patients with CC genotype( 0) was lower than those in AA( 9. 37%) and AC( 12. 50%) genotype carriers,but the differences were not statistically significant. The incidences of hepatic disorders and electrolyte disorders in children with CC genotype( 33. 33% and 16. 67%,respectively) were higher than those in AA( 12. 50% and 14. 58%) and AC( 18. 75% and 3. 13%) genotype carriers. The incidences of other adverse events in patients with CC genotype were lowerthan those in AA and AC genotype carriers. The differences in the incidences of MTX toxicities among three genotypes did not achieve statistical significance. Conclusion MTHFR rs1801131 A > C polymorphisms were significantly associated with clinical prognosis of ALL children. There were no significant associations between the investigated polymorphisms and toxicities of MTX.
引文
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[7]郑苗苗,岳丽杰,陈小文,等.急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系[J].广东医学,2015,36(3):413-416.
[8]FUKUSHIMA H,FUKUSHIMA T,SAKAI A,et al. Polymorphisms of MTHFR associated with higher relapse/death ratio and delayed weekly MTX administration in pediatric lymphoid malignancies[J/OL]. Leuk Res Treatment,2013,2013:238528. 2013-12-10[2018-07-22]. https://www. hindawi. com/journals/lrt/2013/238528/.
[9]EFRATI E,ELKIN H,NAHUM S,et al. Population distribution of methylenetetrahydrofolate reductase(MTHFR)C677T and A1298C risk alleles for methotrexate toxicity in Israel[J]. Rheumatol Int,2013,33(4):1001-1004.
[2]KALUZNA E,STRAUSS E,ZAJAC-SPYCHALA O,et al. Functional variants of gene encoding folate metabolizing enzyme and methotrexate-related toxicity in children with acute lymphoblastic leukemia[J/OL]. Eur J Pharmacol,2015,769:93-99. 2018-11-01[2018-07-22]. https://linkinghub. elsevier. com/retrieve/pii/S0014-2999(15)30336-8.
[3]中华医学会儿科学分会血液学组,中华儿科杂志编辑委员会.儿童急性淋巴细胞白血病诊疗建议(第三次修订草案)[J].中华儿科杂志,2006,44(5):392-395.
[4]魏盈盈,焦溦溦,程思,等.大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的血药浓度与不良反应的相关性[J].中国医院药学杂志,2014,34(22):1915-1918.
[5]叶阿里,张海燕,窦亚玲,等.基质辅助激光解吸电离飞行时间质谱技术检测药物代谢酶基因多态性平台的建立[J].现代检验医学杂志,2016,31(5):30-33.
[6]MEI L,ONTIVEROS E P,GRIFFITHS E A,et al. Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy[J]. Blood Rev,2015,29(4):243-249.
[7]郑苗苗,岳丽杰,陈小文,等.急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系[J].广东医学,2015,36(3):413-416.
[8]FUKUSHIMA H,FUKUSHIMA T,SAKAI A,et al. Polymorphisms of MTHFR associated with higher relapse/death ratio and delayed weekly MTX administration in pediatric lymphoid malignancies[J/OL]. Leuk Res Treatment,2013,2013:238528. 2013-12-10[2018-07-22]. https://www. hindawi. com/journals/lrt/2013/238528/.
[9]EFRATI E,ELKIN H,NAHUM S,et al. Population distribution of methylenetetrahydrofolate reductase(MTHFR)C677T and A1298C risk alleles for methotrexate toxicity in Israel[J]. Rheumatol Int,2013,33(4):1001-1004.