急性髓细胞白血病细胞和分子遗传学特征
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摘要
[目的]
1.单中心研究中国4241例初治急性髓细胞白血病(de no AML)患者细胞遗传学分布特征,比较与亚洲其他国家和西方国家差异。
2.研究430例初治AML患者16种基因突变发生率,分析基因突变与患者临床资料、MICM分型、危险分组及对预后的影响。
3.研究EZH2基因突变在714例AML患者中发生率和临床意义。
[方法]
1.分析1985年4月至2010年11月于苏州大学附属第一医院4196例经MICM分型确诊的初治AML患者骨髓细胞遗传学特征。采用R显带核型分析技术,并按照国际人类细胞遗传学术语命名法(ISCN2009)进行核型突变命名。
2.采集430例AML患者骨髓单个核细胞,采用基因组DNA-PCR方法扩增C-KIT、NPM1、FLT3-TKD、FLT3-ITD、MLL-PTD、EZH2、RUNX1、 ASXL1、IDH1、IDH2、NRAS、CBL、WT1、TET2、DNMT3和JAK2基因,采用直接基因测序分析基因突变。随访患者临床与实验室资料及疗效、复发及长期生存情况。
3.对714例AML患者骨髓单个核细胞基因组DNA进行PCR方法扩增EZH2基因2～20外显子,并通过DNA直接测序法检测EZH2的突变,并分析EZH2基因突变和患者临床特征相关性及对预后的影响。
[结果]
1.单中心中国急性髓细胞白血病细胞遗传学特征
4196例AML患者(98.9%)成功的进行了细胞遗传学的分析,其中2405例(57.3%)患者核型异常,并检测出65种新的核型异位突变。在各种核型异常中,t(15；17)居于首位,占19.3%,其次为t(8；21)(14.3%)、复杂核型(5.3%)、+8(3.2%);本中心t(15；17)和t(8；21)异常比例与其他东亚国家相似,均明显高于北欧和美国；与西方国家相比,M3亚型比例偏高,而M4亚型比例偏低。
2.16种基因突变的发生率及其临床意义。
430例AML患者中,77.2.0%患者具有一种及一种以上基因突变发生,而在正常核型中,基因突变比例高达84.3%。RUNX1和IDH1倾向于发生在老年人(P=0.004,P=0.038),而MLL-PTD绝大多数发生于男性(12/14,85.7%)。NPM1(P<0.0001), FLT3-ITD (P<0.0001)、DNMT3A (P=0.021)突变与血象高白细胞(30.0×109/L)具有明显的相关性;MLL-PTD (P<0.0001)和EZH2(p=0.023)突变的发生与患者初诊时骨髓原始细胞比例低于30%具有显著相关性；MLL-PTD (P<0.0001), RUNX1(p=0.015)突变绝大多数发生于髓单核性免疫表型AML;73.5%C-KIT突变发生于CBF阳性AML (P<0.0001),81.1%NPM1、63.8%IDH2和85.2%DNMT3A突变发生于正常核型AML.
各基因突变相关性分析显示,NPM1突变与FLT3-ITD(37/99, P<0.0001)、IDH1(13/20, P<0.0001)、IDH2(24/47, P<0.0001)、TET2(17/47, P=0.007)和DNMT3A (18/27, P<0.0001)突变具有显著相关。
预后分析显示存在FLT3-ITD、IDH1和NRAS突变患者CR率明显低下,P值分别为0.007、0.031和0.031,FLT3-ITD、NRAS突变和危险分组是CR率的独立影响因素(P<0.0001,p=0.003, P=0.006respectively); Kaplan-Meier生存分析发现NPM1、 FLT3-ITD、MLL-PTD、RUNX1、IDH1、IDH2、NRAS和DNMT3A突变患者与不良预后相关,无病生存率(EFS):P=0.0148,P=0.0164,P=0.0018,P=0.0015,P=0.0213, P=0.0116,P=0.0001,P<0.0001;总生存率(OS:P=0.0077,P=0.0039,P=0.0177, P=0.0150,P=0.0014,P=0.0159,P<0.0001, P=0.0001。
多因素Cox回归分析显示,FLT3-ITD、NRAS、IDH2突变,年龄和危险分类是独立预后因素,EFS:P值分别为P<0.0001、0.029、0.046、<0.0001、<0.0001;OS:P值分别为<0.0001、0.001、0.005、<0.0001、<0.0001。
3.EZH2发生率及其临床意义。
714例AML患者中,13例检测到EZH2基因突变,突变率为1.8%,更易存在于男性(11/13),具有统计学意义(P=0.033)。单因素分析显示骨髓原始细胞<30%组EZH2突变率为14.3%(4/28),而原始细胞≥30%组患者EZH2突变率仅1.3%(9/686),两者存在着显著的差异(P<0.0001)。具有-7和7q-核型异常的患者EZH2突变率(2/22,7.7%)明显高于不伴有-7和7q-核型异常者(11/672,1.65%),(P=0.025)。
虽然EZH2突变组患者无病生存时间和总生存时间均低于野生组,但EZH2突变对AML患者CR率、无病生存率(EFS)和总生存率(OS)影响无统计学意义,p值>0.05。因EZH2突变发生在AML患者为小概率事件,经预后加权分析后显示,EZH2突变对预后的影响尚不能定论。
[结论]
1.与西方国家相比,我单位AML患者发病年龄更加年轻。东亚地区AML患者更倾向于FAB M3亚型及预后较好细胞核型,t(15；17)和t(8；21)。
2.基因突变与AML的临床特征具有一定相关性并且是AML预后重要影响因。
3. EZH2突变作为AML患者重现性基因遗传学异常,与发病时骨髓原始细胞比例低于30%及-7/del(7q)核型异常具有显著相关性,其对预后的影响尚不清楚。
4.对AML预后危险分组评估和个体化治疗方案的制定过程中,应该对包括年龄,身体状况、临床和MICM特征,尤其细胞和分子遗传学因素进行综合分析。
[Objective]
1. To analyze cytogenetic characters on4241consecutive and unselected de novo AML patients from a single center in China and compare our results with that of other Asian and western countries
2. To investigated the prevalence of16gene mutations including C-KIT, NPM1, FLT3-TKD, FLT3-ITD, MLL-PTD, EZH2, RUNX1, ASXL1, IDH1, IDH2, NRAS, CBL, WT1, TET2, DNMT3A and JAK2on the molecular level by sequencing coding exons in a cohort of430de novo AML patients, analyzed the relationship with clinical features, MICM characters and risk-status categories, evaluated the correlation among gene mutations and the prognostic relevance with treatment.
3. To determine the incidence and clinical implications of somatic EZH2mutations in714patients with de novo AML.
[Methods]
1. From April1985to November2011, samples from4196newly diagnosed patients with de novo AML were received at the cytogenetic laboratory of the First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology for cytogenetic analysis. R-banded karyotypic analyses were then performed according to standard procedures of our laboratory.Chromosomal abnormalities were described according to the International System for Human Cytogenetic Nomenclature (ISCN2009).
2. Genomic DNA of all430patients was extracted from frozen bone marrow mononuclear cells (BMMCs) after Ficoll gradient centrifugation using standard procedures. Mutations of C-KIT, NPM1, FLT3-TKD, FLT3-ITD, MLL-PTD,EZH2, RUNX1, ASXL1, IDH1, IDH2, NRAS, CBL, WT1, TET2, DNMT3and JAK2were analyzed by PCR amplification followed by direct DNA sequencing. The clinical and lab data of these cases were collected, and their clinical characteristics therapies and survival prognosis were analyzed.
3. EZH2mutations were analyzed by PCR amplification of the entire coding region of PHF6exons2-10followed by direct bidirectional DNA sequencing in714AML patients from January2005to December2010.
[Results]
1. Cytogenetic characters on4241de novo AML patients from a single center Karyotypic analyses were successfully performed in4196patients (98.9%) at diagnosis. Chromosome abnormalities were detected in2405patients (57.3%). Besides the aberrations previously reported in the literature,65novel translocations were observed in this study. t(15;17) represented the most frequent anomaly(19.3%) in our cohort, followed by t(8;21)(14.3%), complex (5.3%),+8(3.2%). The percentage of t(15;17) and t(8;21) was comparable with that in most East Asian countries, which was obviously higher than reported in Central-North Europe and the United States. Among the FAB subtype, the frequency of M3was higher while M4was lower compared with that of western countries.
2. Gene mutation patterns
77.2.0%of430AML patients and84.3%of178normal karyotype AMLs were found to have at least one mutation. RUNX1and IDH1mutation had the tendency to occur in the old age (P=0.004, P=0.038) and MLL-PTD mutation exclusively in male patients12/14(85.7%). NPM1, FLT3-ITD, DNMT3A mutations were significantly associated to high WBC count (30.0×109/L)(P<0.0001, P<0.0001and P=0.021respectively), MLL-PTD and EZH2to less percentage of blasts in bone marrow(<30%)(P<0.0001and p=0.023) and MLL-PTD, RUNX1mostly to BM immunophenotype of both myeloid and monocytic (P<0.0001and p=0.015). C-KIT mutation overwhelming occurred in core binding factor (CBF) leukemias (73.5%)(P<0.0001), while NPM1(81.1%), IDH2(63.8%) and DNMT3A (85.2%) mostly occurred in normal karyotype AMLs.
NPM1mutation often overlapped with the others genes, associated with FLT3-ITD (37/99, P<0.0001), IDH1(13/20, P<0.0001), IDH2(24/47, P<0.0001), TET2(17/47, P=0.007) and DNMT3A (18/27, P<0.0001).
Prognosis analysis showed FLT3-ITD, IDH1, NRAS mutations were associated with a significant lower CR rate (P=0.007,0.031and0.031, respectively), FLT3-ITD, NRAS and risk-status subgroup were independent influence factors for CR rate (P<0.0001, p=0.003, P=0.006respectively). By Kaplan-Meier survival analysis, NPM1, FLT3-ITD, MLL-PTD, RUNX1, IDH1, IDH2, NRAS and DNMT3A mutations predicted the poor EFS and OS(EFS:P=0.0148, P=0.0164, P=0.0018, P=0.0015, P=0.0213, P=0.0116, P=0.0001and P<0.0001, respectively and OS:P=0.0077,P=0.0039, P=0.0177, P=0.0150, P=0.0014, P=0.0159, P<0.0001, P=0.0001, respectively).
In a multivariate Cox regression model, mutations of FLT3-ITD, NRAS, IDH2, age and risk-status category were revealed independent prognostic significance (EFS: P<0.0001,0.029,0.046,<0.0001<0.0001;OS:<0.0001,0.001,0.005,<0.0001,<0.0001).
3. Prevalence and prognostic value of somatic EZH2mutations in714patients with de novo AML.
EZH2mutations were identified in13/714(1.8%) of AML patients and occurred more in males (P=0.033). The presence of EZH2mutations was significantly associated with lower blast percentage (21-30%) in bone marrow (P<0.0001) and-7/del(7q)(P=0.025). There were no differences in the incidence of mutations in13genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2mutations.
Because of rarity of EZH2mutations in de novo AML, the prognostic impact of EZH2mutations in AML is still uncertain, and will need to be assessed in larger cohorts of patients collected on multi-center co-operative studies, though there were no significant difference on EFS and OS between EZH2mutated patients and wild-type in this study.
[Conclusions]
1. Age at diagnosis of AML was much younger than those from the western countries. AML patients of the East Asian population may predispose to have a favorable karyotype and the M3subtype.
2. Gene mutations were demonstrated related with clinical features and valuable prognostic markers of AML.
3. Somatic mutations of EZH2may play an important role in pathogenesis of de novo AML patients with-7/del(7q) or with21-30%of blasts in BM.The prognostic impact of EZH2mutations in AML is still uncertain, though there were no significant difference on EFS and OS between EZH2mutated patients and wild-type in this study.
4. To evaluate exactly prognosis risk status and formulate the personal therapeutic regimen, synthetic analysis of all the factors including age, physical condition, clinical feathers, and MICM characters, especially in cytogenetics and genetic mutation pattern, should extremely been taken into account in advanced
1.单中心研究中国4241例初治急性髓细胞白血病(de no AML)患者细胞遗传学分布特征,比较与亚洲其他国家和西方国家差异。
2.研究430例初治AML患者16种基因突变发生率,分析基因突变与患者临床资料、MICM分型、危险分组及对预后的影响。
3.研究EZH2基因突变在714例AML患者中发生率和临床意义。
[方法]
1.分析1985年4月至2010年11月于苏州大学附属第一医院4196例经MICM分型确诊的初治AML患者骨髓细胞遗传学特征。采用R显带核型分析技术,并按照国际人类细胞遗传学术语命名法(ISCN2009)进行核型突变命名。
2.采集430例AML患者骨髓单个核细胞,采用基因组DNA-PCR方法扩增C-KIT、NPM1、FLT3-TKD、FLT3-ITD、MLL-PTD、EZH2、RUNX1、 ASXL1、IDH1、IDH2、NRAS、CBL、WT1、TET2、DNMT3和JAK2基因,采用直接基因测序分析基因突变。随访患者临床与实验室资料及疗效、复发及长期生存情况。
3.对714例AML患者骨髓单个核细胞基因组DNA进行PCR方法扩增EZH2基因2～20外显子,并通过DNA直接测序法检测EZH2的突变,并分析EZH2基因突变和患者临床特征相关性及对预后的影响。
[结果]
1.单中心中国急性髓细胞白血病细胞遗传学特征
4196例AML患者(98.9%)成功的进行了细胞遗传学的分析,其中2405例(57.3%)患者核型异常,并检测出65种新的核型异位突变。在各种核型异常中,t(15；17)居于首位,占19.3%,其次为t(8；21)(14.3%)、复杂核型(5.3%)、+8(3.2%);本中心t(15；17)和t(8；21)异常比例与其他东亚国家相似,均明显高于北欧和美国；与西方国家相比,M3亚型比例偏高,而M4亚型比例偏低。
2.16种基因突变的发生率及其临床意义。
430例AML患者中,77.2.0%患者具有一种及一种以上基因突变发生,而在正常核型中,基因突变比例高达84.3%。RUNX1和IDH1倾向于发生在老年人(P=0.004,P=0.038),而MLL-PTD绝大多数发生于男性(12/14,85.7%)。NPM1(P<0.0001), FLT3-ITD (P<0.0001)、DNMT3A (P=0.021)突变与血象高白细胞(30.0×109/L)具有明显的相关性;MLL-PTD (P<0.0001)和EZH2(p=0.023)突变的发生与患者初诊时骨髓原始细胞比例低于30%具有显著相关性；MLL-PTD (P<0.0001), RUNX1(p=0.015)突变绝大多数发生于髓单核性免疫表型AML;73.5%C-KIT突变发生于CBF阳性AML (P<0.0001),81.1%NPM1、63.8%IDH2和85.2%DNMT3A突变发生于正常核型AML.
各基因突变相关性分析显示,NPM1突变与FLT3-ITD(37/99, P<0.0001)、IDH1(13/20, P<0.0001)、IDH2(24/47, P<0.0001)、TET2(17/47, P=0.007)和DNMT3A (18/27, P<0.0001)突变具有显著相关。
预后分析显示存在FLT3-ITD、IDH1和NRAS突变患者CR率明显低下,P值分别为0.007、0.031和0.031,FLT3-ITD、NRAS突变和危险分组是CR率的独立影响因素(P<0.0001,p=0.003, P=0.006respectively); Kaplan-Meier生存分析发现NPM1、 FLT3-ITD、MLL-PTD、RUNX1、IDH1、IDH2、NRAS和DNMT3A突变患者与不良预后相关,无病生存率(EFS):P=0.0148,P=0.0164,P=0.0018,P=0.0015,P=0.0213, P=0.0116,P=0.0001,P<0.0001;总生存率(OS:P=0.0077,P=0.0039,P=0.0177, P=0.0150,P=0.0014,P=0.0159,P<0.0001, P=0.0001。
多因素Cox回归分析显示,FLT3-ITD、NRAS、IDH2突变,年龄和危险分类是独立预后因素,EFS:P值分别为P<0.0001、0.029、0.046、<0.0001、<0.0001;OS:P值分别为<0.0001、0.001、0.005、<0.0001、<0.0001。
3.EZH2发生率及其临床意义。
714例AML患者中,13例检测到EZH2基因突变,突变率为1.8%,更易存在于男性(11/13),具有统计学意义(P=0.033)。单因素分析显示骨髓原始细胞<30%组EZH2突变率为14.3%(4/28),而原始细胞≥30%组患者EZH2突变率仅1.3%(9/686),两者存在着显著的差异(P<0.0001)。具有-7和7q-核型异常的患者EZH2突变率(2/22,7.7%)明显高于不伴有-7和7q-核型异常者(11/672,1.65%),(P=0.025)。
虽然EZH2突变组患者无病生存时间和总生存时间均低于野生组,但EZH2突变对AML患者CR率、无病生存率(EFS)和总生存率(OS)影响无统计学意义,p值>0.05。因EZH2突变发生在AML患者为小概率事件,经预后加权分析后显示,EZH2突变对预后的影响尚不能定论。
[结论]
1.与西方国家相比,我单位AML患者发病年龄更加年轻。东亚地区AML患者更倾向于FAB M3亚型及预后较好细胞核型,t(15；17)和t(8；21)。
2.基因突变与AML的临床特征具有一定相关性并且是AML预后重要影响因。
3. EZH2突变作为AML患者重现性基因遗传学异常,与发病时骨髓原始细胞比例低于30%及-7/del(7q)核型异常具有显著相关性,其对预后的影响尚不清楚。
4.对AML预后危险分组评估和个体化治疗方案的制定过程中,应该对包括年龄,身体状况、临床和MICM特征,尤其细胞和分子遗传学因素进行综合分析。
[Objective]
1. To analyze cytogenetic characters on4241consecutive and unselected de novo AML patients from a single center in China and compare our results with that of other Asian and western countries
2. To investigated the prevalence of16gene mutations including C-KIT, NPM1, FLT3-TKD, FLT3-ITD, MLL-PTD, EZH2, RUNX1, ASXL1, IDH1, IDH2, NRAS, CBL, WT1, TET2, DNMT3A and JAK2on the molecular level by sequencing coding exons in a cohort of430de novo AML patients, analyzed the relationship with clinical features, MICM characters and risk-status categories, evaluated the correlation among gene mutations and the prognostic relevance with treatment.
3. To determine the incidence and clinical implications of somatic EZH2mutations in714patients with de novo AML.
[Methods]
1. From April1985to November2011, samples from4196newly diagnosed patients with de novo AML were received at the cytogenetic laboratory of the First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology for cytogenetic analysis. R-banded karyotypic analyses were then performed according to standard procedures of our laboratory.Chromosomal abnormalities were described according to the International System for Human Cytogenetic Nomenclature (ISCN2009).
2. Genomic DNA of all430patients was extracted from frozen bone marrow mononuclear cells (BMMCs) after Ficoll gradient centrifugation using standard procedures. Mutations of C-KIT, NPM1, FLT3-TKD, FLT3-ITD, MLL-PTD,EZH2, RUNX1, ASXL1, IDH1, IDH2, NRAS, CBL, WT1, TET2, DNMT3and JAK2were analyzed by PCR amplification followed by direct DNA sequencing. The clinical and lab data of these cases were collected, and their clinical characteristics therapies and survival prognosis were analyzed.
3. EZH2mutations were analyzed by PCR amplification of the entire coding region of PHF6exons2-10followed by direct bidirectional DNA sequencing in714AML patients from January2005to December2010.
[Results]
1. Cytogenetic characters on4241de novo AML patients from a single center Karyotypic analyses were successfully performed in4196patients (98.9%) at diagnosis. Chromosome abnormalities were detected in2405patients (57.3%). Besides the aberrations previously reported in the literature,65novel translocations were observed in this study. t(15;17) represented the most frequent anomaly(19.3%) in our cohort, followed by t(8;21)(14.3%), complex (5.3%),+8(3.2%). The percentage of t(15;17) and t(8;21) was comparable with that in most East Asian countries, which was obviously higher than reported in Central-North Europe and the United States. Among the FAB subtype, the frequency of M3was higher while M4was lower compared with that of western countries.
2. Gene mutation patterns
77.2.0%of430AML patients and84.3%of178normal karyotype AMLs were found to have at least one mutation. RUNX1and IDH1mutation had the tendency to occur in the old age (P=0.004, P=0.038) and MLL-PTD mutation exclusively in male patients12/14(85.7%). NPM1, FLT3-ITD, DNMT3A mutations were significantly associated to high WBC count (30.0×109/L)(P<0.0001, P<0.0001and P=0.021respectively), MLL-PTD and EZH2to less percentage of blasts in bone marrow(<30%)(P<0.0001and p=0.023) and MLL-PTD, RUNX1mostly to BM immunophenotype of both myeloid and monocytic (P<0.0001and p=0.015). C-KIT mutation overwhelming occurred in core binding factor (CBF) leukemias (73.5%)(P<0.0001), while NPM1(81.1%), IDH2(63.8%) and DNMT3A (85.2%) mostly occurred in normal karyotype AMLs.
NPM1mutation often overlapped with the others genes, associated with FLT3-ITD (37/99, P<0.0001), IDH1(13/20, P<0.0001), IDH2(24/47, P<0.0001), TET2(17/47, P=0.007) and DNMT3A (18/27, P<0.0001).
Prognosis analysis showed FLT3-ITD, IDH1, NRAS mutations were associated with a significant lower CR rate (P=0.007,0.031and0.031, respectively), FLT3-ITD, NRAS and risk-status subgroup were independent influence factors for CR rate (P<0.0001, p=0.003, P=0.006respectively). By Kaplan-Meier survival analysis, NPM1, FLT3-ITD, MLL-PTD, RUNX1, IDH1, IDH2, NRAS and DNMT3A mutations predicted the poor EFS and OS(EFS:P=0.0148, P=0.0164, P=0.0018, P=0.0015, P=0.0213, P=0.0116, P=0.0001and P<0.0001, respectively and OS:P=0.0077,P=0.0039, P=0.0177, P=0.0150, P=0.0014, P=0.0159, P<0.0001, P=0.0001, respectively).
In a multivariate Cox regression model, mutations of FLT3-ITD, NRAS, IDH2, age and risk-status category were revealed independent prognostic significance (EFS: P<0.0001,0.029,0.046,<0.0001<0.0001;OS:<0.0001,0.001,0.005,<0.0001,<0.0001).
3. Prevalence and prognostic value of somatic EZH2mutations in714patients with de novo AML.
EZH2mutations were identified in13/714(1.8%) of AML patients and occurred more in males (P=0.033). The presence of EZH2mutations was significantly associated with lower blast percentage (21-30%) in bone marrow (P<0.0001) and-7/del(7q)(P=0.025). There were no differences in the incidence of mutations in13genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2mutations.
Because of rarity of EZH2mutations in de novo AML, the prognostic impact of EZH2mutations in AML is still uncertain, and will need to be assessed in larger cohorts of patients collected on multi-center co-operative studies, though there were no significant difference on EFS and OS between EZH2mutated patients and wild-type in this study.
[Conclusions]
1. Age at diagnosis of AML was much younger than those from the western countries. AML patients of the East Asian population may predispose to have a favorable karyotype and the M3subtype.
2. Gene mutations were demonstrated related with clinical features and valuable prognostic markers of AML.
3. Somatic mutations of EZH2may play an important role in pathogenesis of de novo AML patients with-7/del(7q) or with21-30%of blasts in BM.The prognostic impact of EZH2mutations in AML is still uncertain, though there were no significant difference on EFS and OS between EZH2mutated patients and wild-type in this study.
4. To evaluate exactly prognosis risk status and formulate the personal therapeutic regimen, synthetic analysis of all the factors including age, physical condition, clinical feathers, and MICM characters, especially in cytogenetics and genetic mutation pattern, should extremely been taken into account in advanced
引文
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