TPMT、NUDT15基因多态性对成人急性淋巴细胞白血病患者6-巯基嘌呤耐受性的影响  

Effect of genetic polymorphism of TPMT and NUDT15 on the tolerance of 6-mercaptopurine therapy in adult acute lymphoblastic leukemia

作　　者：郝其姗 王哲 房秋云 弓晓媛 刘凯奇 李艳 魏辉 王迎 李庆华 王敏 田征 王建祥 秘营昌 Hao Qishan;Wang Zhe;Fang Qiuyun;Gong Xiaoyuan;Liu Kaiqi;Li Yan;Wei Hlui;Wang Ying;Li Qimghua;Wang Min;Tian Zheng;Wang Jianxiang;Mi Yingchang(Institute of Hematology&Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Tianjin 300020)

机构地区：[1]中国医学科学院、北京协和医学院血液病医院(中国医学科学院血液学研究所),实验血液学国家重点实验室,国家血液系统疾病临床医学研究中心,天津300020

出　　处：《中华血液学杂志》2021年第11期911-916,共6页Chinese Journal of Hematology

基　　金：国家科技重大专项(2017ZX09304024);国家重点研发计划(2019YFC0840605);中央高校基本科研业务经费课题(332021059)。

摘　　要：目的探讨TPMT*2 rs1800462、TPMT*3B rs1800460、TPMT*3C rs1142345和NUDT15 rs116855232基因多态性对成人急性淋巴细胞白血病(ALL)患者6-巯基嘌呤(6-MP)耐受性的影响。方法选取2015年9月至2019年12月于中国医学科学院血液病医院确诊并接受环磷酰胺、阿糖胞苷和6-MP(CAM方案)治疗的216例成人ALL患者,利用Taqman SNP基因分型方法检测患者的TPMT、NUDT15基因型。结合临床资料,分析基因多态性对ALL治疗中含6-MP方案耐受性的影响。结果216例患者中B-ALL 185例(85.65%)、T-ALL 31例(14.35%)。TPMT*2 rs1800462 CC型216例(100.00%);TPMT*3B rs1800460 CC型216例(100.00%);TPMT*3C rs1142345 TT型209例(96.76%)、TC型7例(3.24%),等位基因突变频率为1.62%。NUDT15 rs116855232 CC型166例(76.85%)、CT型48例(22.22%)、TT型2例(0.93%),等位基因突变频率为12.04%。TPMT*3C rs1142345突变型组(TC+CC型)悬浮红细胞的输注量少于野生型组(CC型)(P=0.036);TPMT*3C rs1142345突变型组出现肝损害(天冬氨酸转氨酶升高)的风险高于野生型组(OR=9.559,95%CI 1.135~80.475,P=0.038)。NUDT15 rs116855232突变型组(CT+TT型)WBC<1×10^(9)/L和中性粒细胞绝对计数<0.5×10^(9)/L的持续时间均长于野生型组(CC型)(P=0.005,P=0.007);突变型组单采血小板的输注量多于野生型组(P=0.014)。结论TMPT、NUDT15基因多态性可以影响成人ALL患者对6-MP的耐受性。治疗前检测患者基因型,进而优化6-MP使用剂量,有助于缩短骨髓抑制时间和减少血制品输注量。临床试验注册:中国临床试验注册中心(ChiCTR-TNC-09000397)Objective To investigate the effect of genetic polymorphisms of TPMT*2 rs1800462.TPMT*3B rsl800460,TPMT*3C rs1142345,and NUDT15rs116855232 on the tolerance of 6-mercaptopurine(6-MP)therapy in adult acute lymphoblastic leukemia(ALL).Methods A total of 2l6adult patients who were diagnosed with ALL and treated with cyclophosphamide,cytarabine,and 6-MP[complementary and alternative medicine(CAM)regimen]from September 2015 to December 2019 wereincluded.Polymorphisms were detected by TaqMan SNP Genotyping Assay.Combined with clinical data.the influence of genetic polymorphism on the tolerance of 6-MP in the treatment of ALL was analyzed.Results Among the 216 patients,185(85.65%)patients had B-ALL and 31(14.35%)patients had T-ALL.216(100%)patients had CC genotype for both TPMT*2 rs1800462 and TPMT*3B rs1800460.Thenumber of TT and TC genotypes for TPMT*3C rs1142345 was 209(96.76%)and 7(3.24%),respectively.The allele frequency was 1.62%for TPMT*3C rs1142345.The number of CC,CT,and TT genotypes forNUDT15 rs116855232 was 166(76.85%),48(22.22%),and 2(0.93%),respectively.The allele frequencywas 12.04%for NUDTl5 rs116855232.The TPMT*3C rs1142345 mutant group(TC+CC genotype)hadless transfusion volume of packed red blood cell than the wild group(CC genotype)(P=0.036),and themutant group(TC+CC genotype)had a higher risk to develop hepatotoxicity(increased aspartateaminotransferase)than the wild group(CC genotype)(OR=9.559,95%CI 1.135-80.475,P=0.038).The durations of white blood cells(WBC)<1×10^(9)L and absolute neutrophil count(ANC)<0.5×10^(9)L inthe NUDT15 rs116855232 mutation group(CT+TT genotype)were longer than that in the wild group(CCgenotype)(P=0.005,P=0.007),and the transfusion volume of apheresis-derived platelets in the mutantgroup(CT+TT type)was greater than that in the wild group(CC genotype)(P=0.014).ConclusionGenetic polymorphism of TMPT and NUDT15 has an effect on the tolerance of 6-MP in the treatment ofadult ALL.Detecting genotypes of patients with ALL before treatment helps to optimize the dosage of 6-MP,which

关 键 词：白血病 淋巴样 成年人 6-巯嘌呤 基因多态性 

分 类 号：R733.71[医药卫生—肿瘤]