急性髓细胞白血病IDH基因突变临床特征及预后意义
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摘要
目的基因突变在急性髓系白血病(acute myelocytic leukemia,AML)患者预后判断方面具有重要意义,其中异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)基因突变与AML的临床特征和预后密切相关。本研究探讨AML患者IDH基因突变的发生率、临床特征及预后意义。方法选取滨州医学院附属医院2015-01-01-2017-01-31经MICM分型确诊的120例初治AML患者,采用骨髓单个核细胞基因组DNA,PCR方法扩增IDHl、IDH2基因4号外显子,基因测序检测IDHl及IDH2基因突变,分析患者临床特征并评估其疗效。结果 120例AML患者中16例检测到IDH基因突变,突变率为13.33%,其中IDHl突变5例(4.17%),IDH2突变11例(9.17%)。未发现有患者同时获得IDHl和IDH2突变。突变组中位年龄55岁,未突变组中位年龄40岁,差异有统计学意义,P=0.000 4;初诊外周血血小板计数为77×10~9 L~(-1),明显高于未突变组的33×10~9 L~(-1),差异有统计学意义,P=0.000 2。IDH突变均发生在AML-M4/M5中,未见其他AML亚型。IDH基因突变与正常核型、NPMl基因突变,尤其是NPMl基因突变未伴FLT3-ITD基因突变的基因型相关。突变组的化疗完全缓解率为50.00%,低于未突变组的79.59%,差异有统计学意义,P<0.01。不伴NPM1基因突变的患者中,IDH基因突变组1年总生存率为50.00%,低于未突变组的86.42%,差异有统计学意义,P<0.01。所有患者中,IDH基因突变组1年总生存率为71.43%,低于未突变组的86.73%,但差异无统计学意义,P>0.05;在正常核型和伴NPM1突变患者中,IDH基因突变组与未突变组1年总生存率差异均无统计学意义,均P>0.05。结论 IDH基因突变更多见于正常核型的AML患者,常与NPMl基因突变相伴随,与患者治疗疗效具有一定相关性,提示是预后不良的分子标志。
OBJECTIVE To explore the prevalence,clinical characteristics and prognostic significance of isocitrate dehydrogenase gene mutations in acute myeloid leukemia(AML)patients.METHODS Polymerase chain reaction(PCR)and direct sequencing were used to sequence exon 4 of IDH gene in 120 AML patients from January 1,2015 to January 31,2017 in Affiliated hospital of Binzhou medical university.RESULTS In a cohort of 120 AML patients,IDH gene mutation was found in 16(13.33%)patients.IDHl and IDH2 mutations were detected in 5(4.17%)patients and 11(9.17%)patients,respectively.None of them had the combined mutations of IDHl and IDH2.The median age was 55 years in mutated group versus 40 years in wild-type group(P<0.01).Blood platelets median level was 77×109 L-1 versus 33×109 L-1(P<0.01).IDH mutations all occurred in AML-M4/M5,other AML subtypes were not observed.IDH gene mutations were associated with cytogenetically normal(CN)AML,NPMl mutations and particularly the genotype of mutated NPMl without FLT3-ITD.IDH mutated patients had a lower complete remission rate than unmutated patients(50.00% vs79.59%,P<0.01).And in the patients without mutated NPM1,IDH gene mutations were associated with a shorter overall survival than non-mutations(50.00%vs 86.42%,P<0.01).In all patients,the overall survival in IDH gene mutation group was lower than in non-mutation group,but the difference was not statistically significant(71.43%vs 86.73%,P>0.05).In the patients with normal karyotype,the overall survival between IDH gene mutation group and non-mutation group was not statistically different(P>0.05),the same result was obtained in the patients with mutated NPM1.CONCLUSIONS IDH gene mutations are more common in AML patients with normal karyotype and are associated with NPMl gene mutation.IDH gene mutations may be poor molecular markers in AML.
OBJECTIVE To explore the prevalence,clinical characteristics and prognostic significance of isocitrate dehydrogenase gene mutations in acute myeloid leukemia(AML)patients.METHODS Polymerase chain reaction(PCR)and direct sequencing were used to sequence exon 4 of IDH gene in 120 AML patients from January 1,2015 to January 31,2017 in Affiliated hospital of Binzhou medical university.RESULTS In a cohort of 120 AML patients,IDH gene mutation was found in 16(13.33%)patients.IDHl and IDH2 mutations were detected in 5(4.17%)patients and 11(9.17%)patients,respectively.None of them had the combined mutations of IDHl and IDH2.The median age was 55 years in mutated group versus 40 years in wild-type group(P<0.01).Blood platelets median level was 77×109 L-1 versus 33×109 L-1(P<0.01).IDH mutations all occurred in AML-M4/M5,other AML subtypes were not observed.IDH gene mutations were associated with cytogenetically normal(CN)AML,NPMl mutations and particularly the genotype of mutated NPMl without FLT3-ITD.IDH mutated patients had a lower complete remission rate than unmutated patients(50.00% vs79.59%,P<0.01).And in the patients without mutated NPM1,IDH gene mutations were associated with a shorter overall survival than non-mutations(50.00%vs 86.42%,P<0.01).In all patients,the overall survival in IDH gene mutation group was lower than in non-mutation group,but the difference was not statistically significant(71.43%vs 86.73%,P>0.05).In the patients with normal karyotype,the overall survival between IDH gene mutation group and non-mutation group was not statistically different(P>0.05),the same result was obtained in the patients with mutated NPM1.CONCLUSIONS IDH gene mutations are more common in AML patients with normal karyotype and are associated with NPMl gene mutation.IDH gene mutations may be poor molecular markers in AML.
引文
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[7]DiNardo CD,Ravandi F,Agresta S,et al.Characteristics,clinical outcome,and prognostic significance of IDH mutations in AML[J].Am J Hematol,2015,90(8):732-736.
[8]Im AP,Sehgal AR,Carroll MP,et al.DNMT3Aand IDH mutations in acute myeloid leukemia and other myeloid malignancies:associations with prognosis and potential treatment strategies[J].Leukemia,2014,28(9):1774-1783.
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[11]应逸,陈建兰,王汉平,等.急性髓细胞白血病NPM1和FLT3-ITD突变检测临床意义分析[J].中华肿瘤防治杂志,2013,20(2):121-124.
[12]DiNardo CD,Ravandi F,Agresta S,et al.Characteristics,clinical outcome,and prognostic significance of IDH mutations in AML[J].Am J Hematol,2015,90(8):732-736.
[13]Patel JP,Gonen M,Figueroa ME,et al.Prognostic relevance of integrated genetic profiling in acute myeloid leukemia[J].N Engl J Med,2012,366(12):1079-1089.
[14]Ravandi F,Patel K,Luthra R,et al.Prognostic significance of alterations in IDH enzyme isoforms in patients with AML treated with high-dose cytarabine andidarubicin[J].Cancer,2012,118(10):2665-2673.
[15]Green CL,Evans CM,Zhao L,et al.The prognostic significance of IDH2mutations in AML depends on the location of the mutation[J].Blood,2011,118(2):409-412.
[16]Willander K,Falk IJ,Chaireti R,et al.Mutations in the isocitrate dehydrogenase 2gene and IDH1SNP 105C>T have a prognostic value in acute myeloid leukemia[J].Biomark Res,2014,2:18.
[2]王蓉娴,吴德沛,陈苏宁,等.急性髓系白血病患者IDHl及IDH2基因突变及临床特征分析[J].中华医学杂志,2013,93(10):751-755.
[3]Medeiros BC,Fathi AT,DiNardo CD,et al.Isocitrate dehydrogenase mutations in myeloid malignancies[J].Leukemia,2017,31(2):272-281.
[4]阮经艳,曾云,狄勇,等.IDH1/2突变诱导急性髓系白血病基因组高甲基化的研究进展[J].重庆医学,2017,46(11):1552-1555.
[5]Xu QY,Li Y,Lv N,et al.Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia:a systematic review and meta-analysis[J].Clin Cancer Res,2017.
[6]Yamaguchi S,Iwanaga E,Tokunaga K,et al.IDH1and IDH2mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1mutation[J].Eur J Haematol,2014,92(6):471-477.
[7]DiNardo CD,Ravandi F,Agresta S,et al.Characteristics,clinical outcome,and prognostic significance of IDH mutations in AML[J].Am J Hematol,2015,90(8):732-736.
[8]Im AP,Sehgal AR,Carroll MP,et al.DNMT3Aand IDH mutations in acute myeloid leukemia and other myeloid malignancies:associations with prognosis and potential treatment strategies[J].Leukemia,2014,28(9):1774-1783.
[9]贾祝霞,周民,晁红颖,等.急性髓系白血病患者IDHl和IDH2基因突变分析[J].中华血液学杂志,2012,33(5):397-401.
[10]Chao HY,Jia ZX,Chen T,et al.IDH2mutations are frequent in Chinese patients with acute myeloid leukemia and associated with NPM1mutations and FAB-M2Subtype[J].Int J Lab Hematol,2012,34(5):502-509.
[11]应逸,陈建兰,王汉平,等.急性髓细胞白血病NPM1和FLT3-ITD突变检测临床意义分析[J].中华肿瘤防治杂志,2013,20(2):121-124.
[12]DiNardo CD,Ravandi F,Agresta S,et al.Characteristics,clinical outcome,and prognostic significance of IDH mutations in AML[J].Am J Hematol,2015,90(8):732-736.
[13]Patel JP,Gonen M,Figueroa ME,et al.Prognostic relevance of integrated genetic profiling in acute myeloid leukemia[J].N Engl J Med,2012,366(12):1079-1089.
[14]Ravandi F,Patel K,Luthra R,et al.Prognostic significance of alterations in IDH enzyme isoforms in patients with AML treated with high-dose cytarabine andidarubicin[J].Cancer,2012,118(10):2665-2673.
[15]Green CL,Evans CM,Zhao L,et al.The prognostic significance of IDH2mutations in AML depends on the location of the mutation[J].Blood,2011,118(2):409-412.
[16]Willander K,Falk IJ,Chaireti R,et al.Mutations in the isocitrate dehydrogenase 2gene and IDH1SNP 105C>T have a prognostic value in acute myeloid leukemia[J].Biomark Res,2014,2:18.