Lyu X D, Guo Z, Li Y W, Hu J Y, Fan R H, Song Y P
Central Lab, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China.
Department of Hematology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450008, China.
Zhonghua Xue Ye Xue Za Zhi. 2020 Jun 14;41(6):483-489. doi: 10.3760/cma.j.issn.0253-2727.2020.06.009.
This study aimed to explore the characteristics and clinical value of clonal heterogeneity in acute myeloid leukemia (AML) . A high-throughput sequencing was carried out to detect 68 related genes in 465 AML patients. Clonal heterogeneity was analyzed based on variant allele frequency (VAF) and flow cytometry results combined with clinical data. Gene mutations were discovered in 338 (81.4%) newly diagnosed patients, and 2 or more clones were significantly increased in patients with DNMT3A, NRAS, and RUNX1 mutations (DNMT3A, (2)=15.23; <0.001; NRAS, (2)=19.866; <0.001; RUNX1, (2)=23.647; <0.001) . The number of clones significantly differed between groups at different ages ((2)=17.505, =0.022) . The proportion of carrying 2 and ≥3 clones increased in patients aged more than 60 years old. There was a significant difference in the clonal heterogeneity between newly diagnosed patients and relapsed or secondary patients ((2)=11.302, =0.010) . Moreover, the proportion of patients with clonal heterogeneity gradually increased according to their prognostic risk ((2)=17.505, =0.022) . Based on the clone analysis, the proportion of primary clones of patients with RUNX1 mutation was higher ((2)=4.527, =0.033) . The analysis of clonal heterogeneity and efficacy demonstrated that patients with three or more clones had significantly lower overall survival (OS) and progression-free survival (PFS) compared to other patients (OS, (2)=13.533; =0.004; PFS, (2)=9.817; =0.020) , while in the intermediate-risk group, patients with a significant clonal heterogeneity also exhibited a significant decrease in PFS ((2)=10.883, =0.012) . Cox regression multivariate analysis revealed that carrying three or more clones was an independent factor affecting prognosis, and OS and PFS were significantly lower than those of patients without clones (OS, =3.296; 95% , 1.568-6.932; =0.002; PFS, =3.241; 95% , 1.411-7.440; =0.006) . Clonal heterogeneity may reflect the biological characteristics of a tumor, suggesting its drug resistance, refractory, and invasiveness, and further evaluate the treatment effect and prognosis of patients.
本研究旨在探讨急性髓系白血病（AML）克隆异质性的特征及临床价值。对465例AML患者进行高通量测序以检测68个相关基因。基于变异等位基因频率（VAF）、流式细胞术结果并结合临床数据对克隆异质性进行分析。在338例（81.4%）新诊断患者中发现基因突变，DNMT3A、NRAS和RUNX1基因突变患者中2个或更多克隆显著增加（DNMT3A，χ² = 15.23；P < 0.001；NRAS，χ² = 19.866；P < 0.001；RUNX1，χ² = 23.647；P < 0.001）。不同年龄组之间的克隆数量存在显著差异（χ² = 17.505，P = 0.022）。60岁以上患者携带2个及≥3个克隆的比例增加。新诊断患者与复发或继发性患者之间的克隆异质性存在显著差异（χ² = 11.302，P = 0.010）。此外，根据预后风险，克隆异质性患者的比例逐渐增加（χ² = 17.505，P = 0.022）。基于克隆分析，RUNX1基因突变患者的初级克隆比例更高（χ² = 4.527，P = 0.033）。克隆异质性与疗效分析表明，与其他患者相比，具有3个或更多克隆的患者总生存期（OS）和无进展生存期（PFS）显著更低（OS，χ² = 13.533；P = 0.004；PFS，χ² = 9.817；P = 0.020），而在中危组中，具有显著克隆异质性的患者PFS也显著降低（χ² = 10.883，P = 0.012）。Cox回归多因素分析显示，携带3个或更多克隆是影响预后的独立因素，OS和PFS显著低于无克隆患者（OS，HR = 3.296；95%CI，1.568 - 6.932；P = 0.002；PFS，HR = 3.241；95%CI，1.411 - 7.440；P = 0.006）。克隆异质性可能反映肿瘤的生物学特性，提示其耐药性、难治性和侵袭性，并可进一步评估患者的治疗效果和预后。
