[Characteristics and prognostic effects of NOTCH1/FBXW7 gene mutations in T-cell acute lymphoblastic leukemia patients].

Publisher: Zhonghua yi xue hui Country of Publication: China NLM ID: 7511141 Publication Model: Print Cited Medium: Print ISSN: 0376-2491 (Print) Linking ISSN: 03762491 NLM ISO Abbreviation: Zhonghua Yi Xue Za Zhi Subsets: MEDLINE

Publication: Beijing : Zhonghua yi xue hui
Original Publication: Beijing : Zhonghua yi xue hui.

F-Box-WD Repeat-Containing Protein 7*/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/genetics ; Receptor, Notch1*/genetics; Adult ; Cell Cycle Proteins/genetics ; Child ; Female ; Humans ; Male ; Mutation ; Prognosis ; Retrospective Studies ; T-Lymphocytes ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/therapeutic use

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.

SB201901094 Joint Construction Project of Henan Medical Science and Technology Research Plan

Local Abstract: [Publisher, Chinese] 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。.

0 (Cell Cycle Proteins)
0 (F-Box-WD Repeat-Containing Protein 7)
0 (FBXW7 protein, human)
0 (NOTCH1 protein, human)
0 (Receptor, Notch1)
0 (SIL-TAL1 fusion protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)

Date Created: 20220629 Date Completed: 20220701 Latest Revision: 20220708

20231215

10.3760/cma.j.cn112137-20211025-02358

35768390