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

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:13.6~24.4个月),儿童野生型组分别为10.0个月(95%CI:8.9~11.1个月)、21.0个月(95%CI:0~51.4个月),差异均无统计学意义(P=0.673、0.434)。结论T-ALL患者NOTCH1/FBXW7基因突变率较高,NOTCH1/FBXW7基因突变组患者血小板计数减低,且具有较好的EFS和OS,NOTCH1/FBXW7基因突变可能作为成人T-ALL患者个体化治疗的一个分层依据。

Objective 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 EFS and OS of adult NOTCH1/FBXW7 gene mutations group were 28.0(95%CI:7.3-48.7)months and 30.0(95%CI:8.9-51.1)months,respectively,which were better than those of adult wild-type group[4.5(95%CI:0-11.6)months and 9.0(95%CI:0-19.1)months](P=0.008 and 0.014).The median EFS and OS of children NOTCH1/FBXW7 gene mutations group were 12.0(95%CI:10.4-13.6)months and 19.0(95%CI:13.6-24.4)months,respectively,and those of wild-type group were 10.0(95%CI:8.9-11.1)months and 21.0(95%CI:0-51.4)months,respectively(P=0.673 and 0.434).Conclusions The mutation rate of NOTCH1/FBXW7 gene is higher in T-ALL patients.Patients with NOTCH1/FBXW7 gene mutations group have lower platelet count and better EFS and OS.NOTCH1/FBXW7 gene mutation may be used as a hierarchical basis for individualized treatment of adult T-ALL patients.