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Title: [Association of Next Generation Sequencing Based Genotypic Profiling with MICM Characteristics in NPM1 Mutated Acute Myeloid Leukemia].
Author: Wang B, Ling Y, Dai L, Gu WY, Zhang XW, Xing SS, Li HQ.
Journal: Zhongguo Shi Yan Xue Ye Xue Za Zhi; 2022 Feb; 30(1):56-60. PubMed ID: 35123604.
Abstract:
OBJECTIVE: To explain the clinicobiological heterogeneity of NPM1 mutated (NPM1^mut) acute myeloid leukemia (AML) by analyzing the association between next-generation sequencing (NGS) profiles and MICM characteristics in patients with this AML subtype. METHODS: Data of 238 NPM1^mut patients with available NGS information on 112 genes related to blood disease was collected, and χ² test and nonparametric test were used to analyze the distribution association between NGS-detecting mutations and conventional MICM parameters. RESULTS: In entire NPM1^mut cohort, totaling 240 NPM1 mutation events were identified, of whom 10 (10/240, 4.2%) were missense mutations, which did not involve any W288 or W290 locus and were found exclusively in NPM1^mut/FLT3-ITD^- group. All but one of these missense mutations (9/10, 90%) were accompanied by AML subtype-defining recurrent cytogenetic or molecular abnormalities, of which 7 cases were in the low risk and 2 in the high risk. NPM1^mut occurred solely as an insertion/deletion (indel) type in the NPM1^mut/FLT3-ITD⁺ group. The incidence of favorable plus unfavorable karyotypes in NPM1^mut/FLT3-ITD^- group was higher than in NPM1^mut/FLT3-ITD⁺ group (6.4% vs. 0, P=0.031). The positive rates of CD34 and CD7 in NPM1^mut/FLT3-ITD⁺ group were significantly higher than in NPM1^mut/FLT3-ITD^- group (CD34: 47.9% vs. 20.6%, P<0.001; CD7: 61.5% vs. 29.9%, P<0.001). Logistic analysis showed that FLT3-ITD independently predicted for CD34⁺ and CD7⁺ [odds ratio (OR)=5.29, 95%CI: 2.64-10.60, P<0.001; OR=3.47, 95%CI: 1.79-6.73, P<0.001; respectively]. Ras-pathway mutations independently predicted for HLA-DR⁺ (OR=4.05, 95%CI: 1.70-9.63, P=0.002), and KRAS mutation for MPO^- (OR=0.18, 95%CI: 0.05-0.62, P=0.007). TET2/IDH1 mutations independently predicted for CD34^- and CD7^- (OR=0.26, 95%CI: 0.11-0.62, P=0.002; OR=0.30, 95%CI: 0.14-0.62, P=0.001; respectively), and MPO⁺ (OR=3.52, 95%CI: 1.48-8.38, P=0.004). DNMT3A-R882 independently predicted for CD7⁺ and HLA-DR⁺ (OR=3.59, 95%CI: 1.80-7.16, P<0.001; OR=13.41, 95%CI: 4.56-39.45, P<0.001; respectively), and DNMT3A mutation for MPO^-(OR=0.35, 95%CI: 1.48-8.38, P=0.004). CONCLUSION: Co-existing FLT3-ITD in NPM1^mut AML independently predicts for CD34⁺ and CD7⁺, co-existing Ras-pathway mutation for HLA-DR⁺ and MPO^-, co-existing TET2/IDH1 mutation for CD34^-, CD7^-, and MPO⁺, and co-existing DNMT3A mutation for HLA-DR⁺, CD7⁺, and MPO^-, thereby providing a new mechanism explanation for the immunophenotypic heterogeneity of these AML patients. 题目: 伴NPM1突变急性髓系白血病二代测序突变基因谱与MICM分型特征关联性分析. 目的: 分析伴NPM1突变（NPM1^mut）急性髓系白血病（AML）患者二代测序（NGS）法检测的突变基因谱与MICM特征间的关系，解释NPM1^mut AML的临床生物学异质性. 方法: 收集苏州大学附属第三医院、南京医科大学附属常州第二人民医院和浙江医院收治的成人初诊AML患者，选取NGS资料完整的NPM1^mut患者238例，采用χ²检验和非参数检验分析NGS突变基因谱与常规MICM参数间的分布关联性. 结果: 全部患者共检出240个NPM1突变事件，其中10个（10/240，4.2%）为错义突变，均不累及W288或W290位点。这10例错义突变事件仅见于NPM1^mut/FLT3-ITD^-者，其中9例（90%）同时合并AML亚型定义的细胞遗传学或分子学异常，且全部为低危（7例）或高危（2例）组。NPM1^mut/FLT3-ITD⁺者NPM1^mut仅为插入/缺失（indel）突变。NPM1^mut/FLT3-ITD^-者高危+低危组异常核型发生率显著高于NPM1^mut/FLT3-ITD⁺者（6.4% vs. 0，P=0.031）。NPM1^mut/FLT3-ITD⁺者CD34和CD7阳性率均显著高于 NPM1^mut/FLT3-ITD^-者（CD34：47.9% vs. 20.6%，P<0.001；CD7：61.5% vs. 29.9%，P<0.001）。Logistic多因素分析显示，FLT3-ITD独立预测CD34⁺（OR=5.29，95%CI：2.64-10.60，P<0.001）和CD7⁺（OR=3.47，95%CI：1.79-6.73，P<0.001）。 Ras通路突变独立预测HLA-DR⁺（OR=4.05，95%CI：1.70-9.63，P=0.002），KRAS突变独立预测MPO^-（OR=0.18，95%CI：0.05-0.62，P=0.007）。TET2/IDH1突变独立预测CD34^-（OR=0.26，95%CI：0.11-0.62，P=0.002）、CD7^-（OR= 0.30，95%CI：0.14-0.62，P=0.001）和MPO⁺（OR=3.52，95%CI：1.48-8.38，P=0.004）。DNMT3A-R882独立预测HLA- DR⁺（OR=13.41，95%CI：4.56-39.45，P<0.001）和CD7⁺（OR=3.59，95%CI：1.80-7.16，P<0.001），DNMT3A突变独立预测MPO^-（OR=0.35，95%CI：1.48-8.38，P=0.004）. 结论: NPM1^mut AML共存FLT3-ITD预测CD34⁺和CD7⁺，共存Ras通路突变预测HLA-DR⁺和MPO^-，共存TET2/IDH1突变预测CD34^-、CD7^-和MPO⁺，共存DNMT3A突变预测HLA-DR⁺、CD7⁺和MPO^-，这为患者免疫表型异质性提供了部分机制解释.

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