诊断学理论与实践 ›› 2024, Vol. 23 ›› Issue (03): 305-312.doi: 10.16150/j.1671-2870.2024.03.008
收稿日期:
2024-04-15
接受日期:
2024-05-08
出版日期:
2024-06-25
发布日期:
2024-06-25
通讯作者:
翟志敏 E-mail: zzzm889@163.com基金资助:
ZHU Weiwei, LI Qian, WU Fan, ZHAI Zhimin()
Received:
2024-04-15
Accepted:
2024-05-08
Published:
2024-06-25
Online:
2024-06-25
摘要:
目的:探讨骨髓增生异常性肿瘤(myelodysplastic syndrome, MDS)患者基因突变与临床特征、预后及急性髓系白血病(acute myeloid leukemia, AML)转化风险间的相关性。方法:回顾性分析100例连续的初治MDS患者的临床资料,采用第二代测序技术检测患者中34种MDS疾病相关突变基因,分析该队列中不同基因的突变发生率及分布情况,探讨高频基因突变(突变率≥10%)与患者临床特征、预后及转化为AML风险之间的关系。结果:100例MDS患者共检出32种基因突变,有84%患者出现至少1种基因突变,基因突变最多见于MDS伴多系病态造血(MDS with multilineage dysplasia, MDS-MLD)患者(39.3%);≥60岁老年患者中有82.8%(53/64)出现基因突变。基因突变中,ASXL1突变发生率最高(26.0%),其他突变率大于10%的基因(高频基因)还包括TET2、U2AF1、DNMT3A、RUNX1、TP53和SF3B1。ASXL1易与RUNX1共突变,与TP53突变共排斥。在基因突变与临床特征相关性分析中,ASXL1突变组骨髓原始细胞比例高于ASXL1未突变组;U2AF1突变组血小板计数少于U2AF1未突变组,老年患者中DNMT3A突变(85.7%)高于年轻患者(14.3%);RUNX1突变组白细胞计数高于RUNX1未突变组;TP53突变组中位国际预后评分系统-修订版(International Prognostic Scoring System-Revised, IPSS-R)评分(6.0分)高于TP53未突变组(4.5分),P=0.016;TP53突变组中位乳酸脱氢酶(lactate dehydrogenase, LDH)数值(420 U/L)高于TP53未突变组(222 U/L) (P=0.002)。本研究中位随访时间为18.6个月,中位生存时间27.1个月,多因素分析表明,TP53突变是总体生存期(overall survival,OS)短的独立危险因素。随访期间,15例(15%)患者发生AML转化,而DNMT3A基因突变是MDS患者发生AML转化的独立危险因素(HR=3.73)。结论:本研究中MDS患者的MDS相关基因突变率为84%,TP53突变与患者不良预后有关,DNMT3A突变与患者易于发生AML转化有关。
中图分类号:
朱维维, 李倩, 吴凡, 翟志敏. 100例骨髓增生异常性肿瘤患者基因突变及其与临床特征间的关系[J]. 诊断学理论与实践, 2024, 23(03): 305-312.
ZHU Weiwei, LI Qian, WU Fan, ZHAI Zhimin. Gene mutations and their relationship with clinical features in 100 patients with myelodysplastic syndrome[J]. Journal of Diagnostics Concepts & Practice, 2024, 23(03): 305-312.
表1
NGS检测基因突变组与无基因突变组MDS患者的临床基线特征比较
Indice | NGS-positive group (n=84) | NGS-negative group (n=16) | Z/χ2 | P |
---|---|---|---|---|
Male/Female | 54/30 | 12/4 | 0.688 | 0.407 |
Age(years) | 66 (17-91) | 65(39-78) | -0.522 | 0.601 |
White blood cell count(×109/L) | 2.52 (0.65-57.34) | 3.26 (0.43-7.84) | -0.823 | 0.411 |
Neutrophil count, NC(×109/L) | 1.21 (0.12-43.92) | 1.23 (0.06-6.20) | -0.606 | 0.544 |
Hemoglobin (g/L) | 64.0 (25-133) | 77.0 (30-109) | -0.809 | 0.419 |
Platelet (×109/L) | 53.5 (3-1086) | 47.5 (5-163) | -0.663 | 0.507 |
Bone marrow blasts (%) | 4.0 (0-18) | 2.0 (0-18) | -0.907 | 0.364 |
Bone marrow blasts≥5% (n/%) | 35 (41.7) | 5 (31.3) | 0.608 | 0.436 |
High-risk karyotype(n/%) | 16 (19.0) | 2 (12.5) | 0.073 | 0.532 |
LDH | 237.5 (76-1453) | 192.0 (89-609) | -1.608 | 0.108 |
LDH>250 U/L (n/%) | 38 (45.2) | 5 (31.3) | 1.073 | 0.3 |
IPSS-R Score | 5.0 (1.5-9.5) | 3.5 (2.0-8.0) | -1.072 | 0.284 |
IPSS-R Score>3.5 (n/%) | 55 (65.5) | 8 (50.0) | 1.381 | 0.24 |
Demethylation therapy (n/%) | 65 (77.4) | 9 (56.3) | 2.118 | 0.146 |
表2
MDS患者总生存率的单因素及多因素分析
Univariate HR (95%CI, P) | Multivariate HR (95%CI, P) | ||
---|---|---|---|
Age (years) | ≥60 | 8.33 (17.49-31.11, 0.004) | 4.01 (1.90-8.44, <0.001) |
<60 | |||
Hemoglobin (g/L) | ≥60 | 3.88 (10.56-36.44, 0.049) | |
<60 | |||
Platelet (×109/L) | ≥80 | 6.30 (16.92-31.68, 0.012) | |
<80 | 2.13 (1.06-4.25, 0.033) | ||
IPSS-R Score | >3.5 | 13.61 (11.19-26.41, 0.001) | 2.69 (1.25-5.78, 0.011) |
≤3.5 | |||
TP53 | Mutation | 6.43 (6.64-10.97, 0.011) | 2.52 (1.20-5.29, 0.014) |
Non-mutation | |||
Transformed to AML | Yes | 12.69 (7.55-23.45, 0.001) | 2.64 (1.31-5.34, 0.007) |
No |
[1] | JIANG M, CHEN M, LIU Q, et al. SF3B1 mutations in myelodysplastic syndromes: A potential therapeutic target for modulating the entire disease process[J]. Front Oncol, 2023, 13:1116438. |
[2] | 中国抗癌协会血液肿瘤专业委员会, 中华医学会血液学分会, 中华医学会病理学分会. 二代测序技术在血液肿瘤中的应用中国专家共识(2018年版)[J]. 中华血液学杂志, 2018, 39(11):881-886. |
Hematologic Oncology Committee of Chinese Anti-Cancer Association, Hematology Branch of Chinese Medical Association, Pathology Branch of Chinese Medical Association. Expert consensus on the application of next-generation sequencing in hematological neoplasms (2018)[J]. Chin J Hematol, 2018, 39(11):881-886. | |
[3] |
SCHMALBROCK L K, DOLNIK A, COCCIARDI S, et al. Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin[J]. Blood, 2021, 137(22):3093-3104.
doi: 10.1182/blood.2020007626 pmid: 33598693 |
[4] | FANG K, QI J, ZHOU M, et al. Clinical characteristics, prognosis, and treatment strategies of TP53 mutations in myelodysplastic syndromes[J]. Clin Lymphoma Myeloma Leuk, 2022, 22(4):224-235. |
[5] | PARK H S, IM K, SHIN D Y, et al. Telomere integrated scoring system of myelodysplastic syndrome[J]. J Clin Lab Anal, 2023, 37(3):e24839. |
[6] | STEENSMA D P. How predictive is the finding of clonal hematopoiesis for the development of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML)?[J]. Best Pract Res Clin Haematol, 2021, 34(4):101327. |
[7] | LI W. Leukemia[M]// LIW. The 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors. Brisbane (AU): Exon Publications, 2022. |
[8] |
HAFERLACH T, NAGATA Y, GROSSMANN V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes[J]. Leukemia, 2014, 28(2):241-247.
doi: 10.1038/leu.2013.336 pmid: 24220272 |
[9] | 李冰, 王静雅, 刘晋琴, 等. 靶向测序检测511例骨髓增生异常综合征患者基因突变[J]. 中华血液学杂志, 2017, 38(12):1012-1016. |
LI B, WANG J Y, LIU J Q, et al. Gene mutations from 511 myelodysplastic syndromes patients performed by targeted gene sequencing[J]. Chin J Hematol, 2017, 38(12):1012-1016. | |
[10] | YANG X, ZHAO H, WU H, et al. Analysis of gene mutation characteristics and its correlation with prognosis in patients with myelodysplastic syndromes[J]. Clin Chim Acta, 2024, 554:117789. |
[11] |
WU K, NIE B, LI L, et al. Bioinformatics analysis of high frequency mutations in myelodysplastic syndrome-related patients[J]. Ann Transl Med, 2021, 9(19):1491.
doi: 10.21037/atm-21-4094 pmid: 34805353 |
[12] | NAZHA A, KOMROKJI R, MEGGENDORFER M, et al. Personalized prediction model to risk stratify patients with myelodysplastic syndromes[J]. J Clin Oncol, 2021, 39(33):3737-3746. |
[13] | 黄龄乐, 颜新宇, 刘兰香, 等. 骨髓增生异常综合征:190例患者的遗传学危险因素及预后分析[J]. 肿瘤, 2023, 43(2):83-95. |
HUANG L L, YAN XY, LIU LX, et al. Myelodysplastic syndrome: an analysis of the genetic risk factors and prognosis of 190 patients[J]. Tumor, 2023, 43(2):83-95. | |
[14] | WANG C, SALLMAN D A. What are the prospects for treating TP53 mutated myelodysplastic syndromes and acute myeloid leukemia[J]. Cancer J, 2022, 28(1):51-61. |
[15] | BERNARD E, NANNYA Y, HASSERJIAN R P, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes[J]. Nat Med, 2020, 26(10):1549-1556. |
[16] | ABAZA Y, ZEIDAN A M. Immune checkpoint inhibition in acute myeloid leukemia and myelodysplastic syndromes[J]. Cells, 2022, 11(14):2249. |
[17] | CHOUDHARY G S, PELLAGATTI A, AGIANIAN B, et al. Activation of targetable inflammatory immune signa-ling is seen in myelodysplastic syndromes with SF3B1 mutations[J]. Elife, 2022, 11:e78136. |
[18] | RUJIRACHAIVEJ P, SIRIBOONPIPUTTANA T, RERKAMNUAYCHOKE B, et al. The frequency of SF3B1 mutations in thai patients with myelodysplastic syndrome[J]. Asian Pac J Cancer Prev, 2018, 19(7):1825-1831. |
[19] | HUGHES C F M, GALLIPOLI P, AGARWAL R. Design, implementation and clinical utility of next generation sequencing in myeloid malignancies: acute myeloid leukaemia and myelodysplastic syndrome[J]. Pathology, 2021, 53(3):328-338. |
[20] |
MADAN V, LI J, ZHOU S, et al. Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes[J]. Am J Hematol, 2020, 95(2):133-143.
doi: 10.1002/ajh.25673 pmid: 31680297 |
[21] | LIANG S, ZHOU X, PAN H, et al. Prognostic value of DNMT3A mutations in myelodysplastic syndromes: a meta-analysis[J]. Hematology, 2019, 24(1):613-622. |
[22] |
JUNG H A, JUNG C W, JANG J H. Mutations in genes affecting DNA methylation enhances responses to decitabine in patients with myelodysplastic syndrome[J]. Korean J Intern Med, 2021, 36(2):413-423.
doi: 10.3904/kjim.2019.385 pmid: 33086776 |
[23] | GOEL H, RAHUL E, GUPTA I, et al. Molecular and genomic landscapes in secondary & therapy related acute myeloid leukemia[J]. Am J Blood Res, 2021, 11(5):472-497. |
[24] | 韩丹丹, 完晓菊, 陈洋, 等. 1例脐血移植植入失败伴免疫性血小板输注无效MDS患者报告[J]. 安徽医学, 2023, 44(8):900-902. |
HAN D D, WAN X J, CHEN Y, et al. 1 Case of failed hematopoietic stem cell transplantation with refractory immune thrombocytopenia in a patient with MDS[J]. Anhui Med, 2023, 44(8):900-902. |
[1] | 周丽华, 沈茹, 屈柯暄, 王爱华, 陈有会, 袁志敏. ABO血型基因第7外显子695 T>C突变导致Bw11亚型的研究[J]. 诊断学理论与实践, 2024, 23(04): 392-397. |
[2] | 李卓含, 黄新韵, 郭睿, 李彪. 18F-FDG PET/CT在滤泡性淋巴瘤诊断和预后评估中的研究进展[J]. 诊断学理论与实践, 2024, 23(04): 439-444. |
[3] | 中国老年医学学会血液学分会MDS专委会. 中国老年骨髓增生异常性肿瘤诊断和治疗专家共识(2024版)[J]. 诊断学理论与实践, 2024, 23(03): 285-296. |
[4] | 王书奎, 顾心亮. tsRNA作为肿瘤诊断和预后标志物的研究进展[J]. 诊断学理论与实践, 2023, 22(05): 413-420. |
[5] | 李一林, 陈杨, 李艳艳, 冯旭娇, 章程, 李健, 沈琳. 循环肿瘤细胞检测在常见恶性肿瘤精准医学中的应用和展望[J]. 诊断学理论与实践, 2023, 22(04): 332-340. |
[6] | 刘英婷, 易红梅, 王雪, 杨春雪, 欧阳斌燊, 许海敏, 王朝夫. 十二指肠型滤泡性淋巴瘤17例临床病理特征及预后分析[J]. 诊断学理论与实践, 2023, 22(04): 362-368. |
[7] | 张兰兰, 杨巧, 聂尊珍, 郭英. 胸膜SMARCA4缺失未分化肿瘤1例报告[J]. 诊断学理论与实践, 2023, 22(04): 389-392. |
[8] | 胡静静, 沈银忠, 刘莉, 卢洪洲. 艾滋病合并播散性非结核分枝杆菌病诊治现状及研究进展[J]. 诊断学理论与实践, 2023, 22(04): 402-406. |
[9] | 徐莉, 高华杰, 杨梦歌, 李悦, 季苏琼. 合并抗TRIM21/Ro52抗体阳性的抗SRP阳性坏死性肌病患者临床特点分析[J]. 诊断学理论与实践, 2023, 22(03): 247-254. |
[10] | 周晓蝶, 陈巍魏, 余波, 王璇, 王建军, 石群立, 饶秋, 鲍炜. 尿路上皮癌的临床病理学特征[J]. 诊断学理论与实践, 2023, 22(03): 292-299. |
[11] | 宋陆茜, 常春康. 2023年美国国立综合癌症网络(NCCN)《骨髓增生异常综合征临床实践指南》(第1版)解读[J]. 诊断学理论与实践, 2023, 22(02): 116-120. |
[12] | 许建昆, 周露婷, 张文净, 许海敏, 王朝夫. CA9在透明细胞肾细胞癌预后评估中的价值[J]. 诊断学理论与实践, 2023, 22(01): 37-43. |
[13] | 王瀚, 陆海迪, 王雷, 丛文铭, 郑建明, 白辰光. 结肠鳞癌2例和腺鳞癌2例临床病理学特征分析[J]. 诊断学理论与实践, 2023, 22(01): 44-49. |
[14] | 王瑾, 郭睿, 李彪, 张晓哲. 18F-FDG PET/CT显像动态评估自然杀伤/T细胞淋巴瘤(鼻型)治疗预后[J]. 诊断学理论与实践, 2022, 21(06): 702-709. |
[15] | 谢吻, 梁怀予, 董磊, 袁菲, 王朝夫, 郭滟. 胰腺导管腺癌重要驱动基因突变与临床病理特征、预后间相关性的分析[J]. 诊断学理论与实践, 2022, 21(05): 581-587. |
阅读次数 | ||||||
全文 |
|
|||||
摘要 |
|
|||||