Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients.
Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients.
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DOI：
10.1186/1756-8722-5-5
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发表时间：
2012-03-07
影响因子：
28.5
通讯作者：
Auewarakul CU
中科院分区：
文献类型：
--
作者：
Chotirat S;Thongnoppakhun W;Promsuwicha O;Boonthimat C;Auewarakul CU
异柠檬酸脱氢酶1和2（IDH 1和IDH 2）代谢基因编码催化异柠檬酸转化为α-酮戊二酸的细胞溶质和线粒体酶。IDH 1和IDH 2的获得性体细胞突变最近在某些类型的脑肿瘤和一小部分急性髓细胞白血病（AML）病例中有报道。采用聚合酶链反应-变性高效液相色谱法（PCR-DHPLC）和直接测序法对230例新诊断的AML患者进行IDH 1和IDH 2杂合突变分析。分析其临床和生物学特征，并与IDH突变状态相关。另外还探索了共存突变，如FLT 3、PML-RARA、RAS、AML 1和NPM 1突变。IDH 1和IDH 2突变的患病率分别为8.7%（20/230）和10.4%（24/230）。在IDH 1突变的病例中鉴定出六种错义突变; p.R132H（n = 8）、p.R132C（n = 6）、p.R132S（n = 2）、p.R132G（n = 2）、p.R132L（n = 1）和p.I99M（n = 1）。在IDH 2突变的病例中发现两个错义突变; p.R140Q（n = 20）和p.R172K（n = 4）。没有患者具有IDH 1和IDH 2双重突变。约18%的细胞遗传学正常的AML和31%的急性早幼粒细胞白血病有IDH突变。IDH突变队列中有一半的核型正常，主要的FAB亚型为AML-M2。有趣的是，与野生型相比，IDH 1和IDH 2突变病例主要具有NPM 1突变（60-74%）（P < 0.001）。极少数IDH突变病例有FLT 3和/或RAS异常，无一例有AML 1突变。年龄较大和血小板计数中位数较高与IDH 2突变显著相关，但未观察到IDH 1或IDH 2突变对患者总生存期的临床影响。总体而言，19%的新诊断AML患者存在IDH基因改变。没有患者同时携带IDH 1和IDH 2突变，表明这些突变是相互排斥的。NPM 1突变是IDH突变患者中主要的共存基因突变。我们目前的数据未能支持IDH突变的预后相关性，尽管这些代谢基因的改变可能在白血病发展中起重要作用。
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes encode cytosolic and mitochondrial enzymes that catalyze the conversion of isocitrate to α-ketoglutarate. Acquired somatic mutations of IDH1 and IDH2 have recently been reported in some types of brain tumors and a small proportion of acute myeloid leukemia (AML) cases. Two-hundred and thirty newly diagnosed AML patients were analyzed for the presence of IDH1 and IDH2 heterozygous mutations by polymerase chain reaction-denaturing high performance liquid chromatography (PCR-DHPLC) followed by direct sequencing. Clinical and biological characteristics were analyzed and correlated to the IDH mutational status. Coexisting mutations such as FLT3, PML-RARA, RAS, AML1, and NPM1 mutations were additionally explored. The prevalence of IDH1 and IDH2 mutations was 8.7% (20/230) and 10.4% (24/230), respectively. Six missense mutations were identified among IDH1-mutated cases; p.R132H (n = 8), p.R132C (n = 6), p.R132S (n = 2), p.R132G (n = 2), p.R132L (n = 1), and p.I99M (n = 1). Two missense mutations were found in IDH2-mutated cases; p.R140Q (n = 20) and p.R172K (n = 4). No patients had dual IDH1 and IDH2 mutations. About 18% of AML with normal cytogenetics and 31% of acute promyelocytic leukemia had IDH mutations. Half of the IDH-mutated cohort had normal karyotype and the major FAB subtype was AML-M2. Interestingly, IDH1- and IDH2-mutated cases predominantly had NPM1 mutations (60-74%) as compared to the wild type (P < 0.001). Very few IDH-mutated cases had FLT3 and/or RAS abnormalities and none of them had AML1 mutations. Older age and higher median platelet counts were significantly associated with IDH2 mutations although the clinical impact of either IDH1 or IDH2 mutations on patients' overall survival could not be observed. Overall, 19% of newly diagnosed AML patients had alterations of IDH genes. No patients concurrently carried both IDH1 and IDH2 mutations suggesting that these mutations were mutually exclusive. NPM1 mutation appears as a major coexisting genetic mutation in IDH-mutated patients. Our present data failed to support the prognostic relevance of IDH mutations although alterations of these metabolic genes potentially have an important role in leukemia development.
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