急性T淋巴细胞白血病患者NOTCH1与FBXW7基因突变特征及对预后的影响  

Characteristics and prognostic effects of NOTCH1/FBXW7 gene mutations in T‑cell acute lymphoblastic leukemia patients

作　　者：邬成业[1] 李玉龙[1] 董晓燕[1] 杨世伟[1] 商保军[1] 张磊[1] 程薇[1] 张琳[1] 朱尊民[1] Wu Chengye;Li Yulong;Dong Xiaoyan;Yang Shiwei;Shang Baojun;Zhang Lei;Cheng Wei;Zhang Lin;Zhu Zunmin(Institute of Hematology,Henan Provincial People′s Hospital,Henan Key Laboratory of Hematopathology,Henan Provincial Engineering Research Center of CAR‑T Cell Treatment and Transformation,Henan Key Laboratory of Stem Cell Differentiation and Modification,Zhengzhou 450003,China)

机构地区：[1]河南省人民医院血液病研究所,河南省血液病理重点实验室,河南省CAR‑T细胞治疗与转化工程研究中心,河南省干细胞分化与调控重点实验室,郑州450003

出　　处：《中华医学杂志》2022年第25期1910-1917,共8页National Medical Journal of China

基　　金：河南省医学科技攻关计划省部共建项目(SB201901094)。

摘　　要：目的分析急性T淋巴细胞白血病(T-ALL)患者NOTCH1与FBXW7基因突变特征及其临床特点对预后的影响。方法回顾性分析2016年3月至2021年3月河南省人民医院有二代基因测序数据的61例T-ALL患者的临床资料,包括男46例,女15例,年龄[M(Q_(1),Q_(3))]为18(11,30)岁。分析T-ALL患者NOTCH1/FBXW7基因突变特征与临床和实验室参数的关系,以及其对无事件生存期(EFS)和总生存期(OS)的影响。结果共34例(55.7%,34/61)患者检出NOTCH1基因突变,其中异二聚体结构域(HD)突变22例(64.7%),脯氨酸/谷氨酸/丝氨酸/苏氨酸结构域(PEST)突变7例(20.6%),同时存在HD与PEST突变5例(14.7%)。9例(14.8%,9/61)患者检出FBXW7基因突变,其中5例同时存在NOTCH1和FBXW7突变。23例(37.7%,23/61)患者为野生型。NOTCH1/FBXW7基因突变组患者与野生型组患者外周血白细胞数量[M(Q_(1),Q_(3))]分别为76.4×10^(9)/L(8.3×10^(9)/L,149.2×10^(9)/L)、54.1×10^(9)/L(5.3×10^(9)/L,156.6×10^(9)/L),血红蛋白水平分别为(89.1±27.1)、(99.5±23.1)g/L,骨髓原始细胞比例[M(Q_(1),Q_(3))]分别为84.5%(69.0%,91.3%)、60.0%(35.0%,80.0%),SIL-TAL1、HOX11、HOX11L2基因表达率分别为7.9%(3/38)比17.4%(4/23)、18.4%(7/38)比4.3%(1/23)、5.3%(2/38)比13.0%(3/23),差异均无统计学意义(均P>0.05);但NOTCH1/FBXW7基因突变组患者血小板水平[M(Q_(1),Q_(3))]为60.5×10^(9)/L(36.8×10^(9)/L,100.3×10^(9)/L),低于野生型组患者的116.0×10^(9)/L(63.0×10^(9)/L,178.0×10^(9)/L)(P=0.018)。伴NOTCH1/FBXW7基因突变组患者的基因突变个数[M(Q_(1),Q_(3))]为2.5(1.8,4.0)个,高于NOTCH1/FBXW7野生型组的0(0,1.0)个(P<0.001)。成人NOTCH1/FBXW7基因突变组患者的中位EFS和OS分别为28.0个月(95%CI:7.3~48.7个月)、30.0个月(95%CI:8.9~51.1个月),均优于成人野生型组患者的4.5个月(95%CI:0~11.6个月)、9.0个月(95%CI:0~19.1个月)(P=0.008、0.014);而儿童NOTCH1/FBXW7基因突变组中位EFS和OS分别为12.0个月(95%CI:10.4~13.6个月)、19.0个月(95%CI:13.6~24Objective To explore the characteristics,clinical features and prognostic effects of NOTCH1/FBXW7 gene mutations in T-cell acute lymphoblastic leukemia(T-ALL)patients.Methods The clinical data of 61 T-ALL patients who underwent second-generation gene sequencing in Henan Provincial People′s Hospital from March 2016 to March 2021 were retrospectively analyzed.There were 46 males and 15 females,with a median age[M(Q_(1),Q_(3))]of 18(11,30)years.The relationship between NOTCH1/FBXW7 gene mutation characteristics,clinical and laboratory parameters and their impact on event free survival(EFS)and overall survival(OS)were analyzed.Results NOTCH1 gene mutations were found in 34 cases(55.7%,34/61),including 22 cases of heterodimer domain(HD)mutations(64.7%),7 cases of proline/glutamate/serine/threonine(PEST)mutations(20.6%),and 5 cases of both HD and PEST mutations(14.7%).FBXW7 gene mutations were detected in 9 cases(14.8%,9/61),of which 5 cases had both NOTCH1 and FBXW7 gene mutations.Twenty-three(37.7%,23/61)cases were wild type.The median white blood cell count of patients in NOTCH1/FBXW7 gene mutations group and wild-type group was 76.4×10^(9)/L(8.3×10^(9)/L,149.2×10^(9)/L),54.1×10^(9)/L(5.3×10^(9)/L,156.6×10^(9)/L),respectively.Moreover,the hemoglobin was(89.1±27.1)g/L and(99.5±23.1)g/L,respectively,and the median proportion of bone marrow primordial cells was 84.5%(69.0%,91.3%)and 60.0%(35.0%,80.0%),respectively.The gene expression rate of SIL-TAL1,Hox11 and Hox11L2 was 7.9%(3/38)vs 17.4%(4/23),18.4%(7/38)vs 4.3%(1/23),5.3%(2/38)vs 13.0%(3/23),respectively(all P>0.05).However,the median platelet level in the NOTCH1/FBXW7 gene mutations group was 60.5×10^(9)/L(36.8×10^(9)/L,100.3×10^(9)/L),which was lower than that in the wild-type group[116.0×10^(9)/L(63.0×10^(9)/L,178.0×10^(9)/L)](P=0.018).The median number of gene mutations in the group with NOTCH1/FBXW7 gene mutations group was 2.5(1.8,4.0),which was more than that in the group without NOTCH1/FBXW7 gene mutations group[0(0,1.0)](P<0.001).The median

关 键 词：白血病 淋巴细胞 急性 T细胞 基因突变 预后 随访研究 

分 类 号：R733.71[医药卫生—肿瘤]