异柠檬酸脱氢酶1突变在胶质瘤免疫治疗中的研究进展

胶质瘤是颅内最常见的原发性恶性肿瘤,其恶性程度高、侵袭性强且预后差,目前亟需新的治疗方法.随着基因测序技术和分子生物技术的发展,研究者发现异柠檬酸脱氢酶1(IDH1)突变在低级别胶质瘤和继发性胶质母细胞瘤中普遍存在.IDH1突变与胶质瘤的发生发展密切相关,是一个值得关注的潜在治疗靶点,可为胶质瘤的治疗提供新的方向.本文...     

异柠檬酸脱氢酶基因突变在脑胶质瘤中的研究进展

异柠檬酸脱氢酶1（IDH1）基因突变在神经胶质瘤中的研究备受关注。IDH1突变导致酶原有活性下降,同时获得将α-酮戊二酸转化为2-羟戊二酸的新功能,并改变了胶质瘤的表观遗传学特征,使胶质瘤代谢重编程,破坏胶质瘤氧化还原稳态。本文简述了IDH1突变在胶质瘤中的机制、诊断价值、预后判断和靶向治疗的国内外研究进展,为IDH1突变深入研究、进一步了解胶质瘤病因及干预措施打下基础,亦为胶质瘤分子水平分类和治疗提供新思路。     

胶质瘤中异柠檬酸脱氢酶的检测及其临床意义

目的 分析异柠檬酸脱氢酶(IDH)在胶质瘤中的突变情况,探讨IDH基因突变对胶质瘤的诊断和预后意义.方法 通过Sanger DNA测序法检测胶质瘤中IDH基因突变情况,同时比较分析IDH突变在不同人群中的突变频率以及对预后的影响.结果 20例胶质瘤患者中发现IDH突变7例,均为IDH1 R132H(C.395G＞ A)突变,突变率为35.0％;存在IDH突变的胶质瘤患者无进展生存期和总生存期优于IDH野生型患者.结论 IDH突变对胶质瘤的辅助诊断和预后判断具有重要的临床意义.     

IDH1突变在胶质瘤中的研究进展

脑胶质瘤是一种常见的颅内原发恶性肿瘤,起源于神经胶质细胞,严重影响人类的健康。随着神经肿瘤分子的发展,异柠檬酸脱氢酶-1（isocitrate dehydrogenase,IDH1）已经成为目前胶质瘤分子标志物的研究热点。IDH1的突变引起2-羟基戊二酸（2-hydroxyglutaric acid,2-HG）异常增高,进一步导致DNA和组蛋白高甲基化,目前已经成为研究的潜在靶点,这一发现能够使胶质瘤的临床治疗获益。本文概述了突变型IDH1的功能,以及目前IDH1突变在胶质瘤发生机制中的作用。此外,还讨论了IDH1突变的胶质瘤的靶向治疗、免疫治疗及临床预后。     

人异柠檬酸脱氢酶1（IDH1）R132 H突变型脑胶质瘤细胞的原代培养及鉴定

目的：建立简单、方便、高效的异柠檬酸脱氢酶1（IDH1）突变型胶质瘤原代细胞体外培养方法,为研究IDH1突变型脑胶质瘤提供细胞模型。方法：样本组织取自低级别脑胶质瘤手术患者,采用组织块法行原代细胞培养,倒置显微镜下观察细胞形态特点;瘤组织应用苏木精－伊红染色法（HE ）和免疫组织化学染色确定胶质瘤病理类型以及级别;原代细胞提取基因组行碱基序列测序以鉴定IDH1突变类型;采用MTT法绘制生长曲线,检测IDH1突变型细胞的体外增殖特性。结果：成功建立WHOⅡ级IDH1 R132H突变型人脑星形胶质细胞瘤细胞株,并可传代。结论：应用合适的方法以及培养液,可以培养出IDH1 R132H突变型人脑胶质瘤原代细胞。     

动态增强MRI纹理特征对胶质瘤级别及异柠檬酸脱氢酶基因表型的判断价值

目的 探讨动态增强磁共振成像(DCE-MRI)纹理特征对胶质瘤级别及异柠檬酸脱氢酶(IDH)基因表型的判断价值。方法 回顾性分析2016年1月至2020年12月于南京医科大学第一附属医院病理确诊为胶质瘤患者(36例)的临床资料,其中低级别胶质瘤(WHOⅠ～Ⅱ级,LGG组)13例,高级别胶质瘤(WHOⅢ～Ⅳ级,HGG组)23例;IDH突变型20例、野生型16例。应用DCE-MRI检查,扫描序列主要包括轴面T1WI及T2WI平扫、轴面DCE和轴面、矢状面、冠状面T1WI增强和磁共振成像液体衰减反转恢复序列(FLAIR)。比较不同级别及IDH基因表型胶质瘤的DCE-MRI纹理特征,利用血流动力学双室模型对感兴趣区(ROI)行渗透性定量分析,得到血浆容积分数(Vp)、血管外细胞外容积分数(Ve)、速率常数(Kep)、双室模型计算生成全脑的容积转运常数(Ktrans)及信号强度-时间曲线下面积(AUC)参数图。基于灰度共生矩阵法,提取能量(Ene)、熵(Ent)及逆差矩(IDM)等纹理特征,获取EneKtrans, EneKep, EneVe, EneVp, EneAUC、EntKtrans、E...     

63例高级别胶质瘤中IDH1和TERT突变状态的预后价值

目的:探讨异柠檬酸脱氢酶-1（IDH1）和端粒酶逆转录酶（TERT）启动子突变对高级别胶质瘤患者的预后价值。方法:选取2014年9月至2017年6月于我院行手术切除且术后病理提示为高级别胶质瘤的患者63例（WHO Ⅲ级27例，Ⅳ级36例），完善临床资料、随访资料、分子检测结果。应用Sanger测序法检测样本中IDH1和TERT启动子突变情况，根据结果将患者分为不同亚组，通过比较其生存期的差异，分析基因突变与患者预后的关系。结果:63例高级别胶质瘤中，IDH1突变型和野生型患者的中位生存期分别为24和10个月，差异有统计学意义（P＜0.01）；TERT突变型和野生型的中位生存期无明显差异（P＞0.05）。IDH1突变为高级别胶质瘤患者预后良好的因素，TERT突变不能单独提示预后，二者联合分析提示:IDH1突变／TERT突变组预后最好，IDH1野生／TERT突变组预后最差，IDH1突变／TERT野生组预后稍好于IDH1野生／TERT野生组，四组间预后有明显差异。结论:IDH1突变的高级别胶质瘤患者有较好的临床预后，在此基础上，TERT启动子突变检测有助于进一步划分其预后分层。     

艾伏尼布治疗异柠檬酸脱氢酶1突变成年人急性髓系白血病临床应用指导原则(2023年版)

艾伏尼布是一种针对异柠檬酸脱氢酶1(IDH1)突变的口服靶向抑制剂,已在美国获批单药治疗IDH1突变初诊或复发难治急性髓系白血病(AML)、胆管癌,或联合阿扎胞苷治疗IDH1突变初诊AML。2022年2月,艾伏尼布在我国获批用于治疗IDH1突变的复发难治AML成年患者。此外,2022年版中国临床肿瘤学会(CSCO)恶性血液病诊疗指南和中国肿瘤整合诊治指南(CACA)也将艾伏尼布纳入IDH1突变初诊AML的治疗推荐。但目前艾伏尼布在我国临床实践中的应用数据有限。为规范艾伏尼布在我国AML患者中的临床应用,专家组成员结合已公布的艾伏尼布相关研究数据,制定了该临床应用指导原则,供临床医生参考。     

全自动免疫组化法与一代测序技术在检测人脑胶质瘤异柠檬酸脱氢酶1突变中的应用价值比较

目的:通过比较全自动免疫组化法与一代测序技术在检测人脑胶质瘤异柠檬酸脱氢酶1(isocitrate dehydrogenase 1,IDH1)基因突变中的优点和缺点,为临床检测脑胶质瘤IDH1基因突变提供有效的方案.方法:收集99例石蜡包埋的临床脑胶质瘤手术标本,采用全自动免疫组化染色机进行IDH1-R132H免疫组化...     

IDH1基因突变在脑胶质瘤中的研究进展

脑胶质瘤是中枢神经系统较常见的肿瘤之一, 尽管目前诊疗技术得到长足的发展, 但疗效仍然不尽如人意。随着分子病理学的发展, 人们越来越关注脑胶质瘤中一些分子水平的异常在诊断和治疗疾病中的意义。近年来研究发现, 脑胶质瘤患者存在高频率的异柠檬酸脱氢酶-1(isocitrate dehydrogenases-1, IDH1)基因突变现象, 而且该突变与脑胶质瘤的诊断分型和临床预后有明确的关系, 对其深入研究, 有望找到脑胶质瘤治疗的新靶点, 对改善当前脑胶质瘤治疗现状有着深远的意义。      

Prognostic Value of MGMT Promoter Methylation and TP53 Mutation in Glioblastomas Depends on IDH1 Mutation

Several molecular markers have been proposed as predictors of outcome in patients with glioblastomas.We investigated the prognostic significance of O6-methylguanine-DNA methyltransferase (MGMT) promotermethylation and TP53 mutation status dependent on isocitrate dehydrogenase 1 (IDH1) mutation in glioblastomapatients. A cohort of 78 patients with histologically confirmed glioblastomas treated with radiation therapy andchemotherapy were reviewed retrospectively. We evaluated the prognostic value of MGMT promoter methylationand TP53 mutation status with regard to progression-free survival (PFS) and overall survival (OS). It was revealedthat mutations in IDH1, promoter methylation of MGMT, TP53 mutation, age, Karnofsky performance status(KFS), and extension of resection were independent prognostic factors. In patients with an IDH1 mutation, thosewith an MGMT methylation were associated with longer PFS (p=0.016) and OS (p=0.013). Nevertheless, thepresence of TP53 mutation could stratify the PFS and OS of patients with IDH1 wild type (p=0.003 and 0.029respectively, log-rank). The MGMT promoter methylation and TP53 mutation were associated with a favorableoutcome of patients with and without mutant IDH1, respectively. The results indicate that glioblastomas withMGMT methylation or TP53 mutations have improved survival that may be influenced by IDH1 mutation status.     

DH1基因检测联合CD-DST药敏指导胶质瘤术后辅助化疗的临床应用分析

摘 要：［目的］ 研究胶质瘤中异柠檬酸脱氢酶1（isocitrate dehydrogenases 1,IDH1）突变和胶滴肿瘤药敏检测技术（CD-DST）结果的关联性及指导术后辅助化疗方案的疗效分析。［方法］收集手术切除并经病理证实的高级别脑胶质瘤组织57例,新鲜标本分别对替莫唑胺等5种化疗药物进行CD-DST检测指导治疗方案,同时采用直接测序法检测肿瘤组织中IDH1基因突变情况,分析两者相关性。以CD-DST检测结果为指导治疗患者57例,比较16例行指导规范治疗与未行指导规范治疗患者的生存情况。［结果］ 57例高级别脑胶质瘤患者中IDH1突变13例（22.8%）,IDH1突变患者中位总生存时间显著性优于IDH1未突变患者（12.0个月 vs 7.5个月,P=0.002）。IDH1突变患者的替莫唑胺、Vp-16、卡铂和卡莫司汀的体外敏感率高于无IDH1突变的患者,而顺铂敏感性在有无突变组差异无统计学意义。CD-DST指导的行规范治疗与未行规范治疗患者的中位总生存时间分别为12个月和8个月,差异无统计学意义（P>0.05）。IDH1突变联合CD-DST敏感指导规范治疗患者的中位总生存时间为14个月,显著性优于其他组别(P=0.019)。［结论］ IDH1基因检测联合CD-DST技术对于高级别脑胶质瘤术后辅助化疗方案具有一定的临床指导价值。     

Knock-in Mice Show Hematopoietic and Epigenetic Effects of IDH1 Mutation

IDH1 mutation leads to increased hematopoietic progenitors and DNA hypermethylation in vivo.     

Mutation Analysis of IDH1/2 Genes in Unselected De novo Acute Myeloid Leukaemia Patients in India - Identification of A Novel IDH2 Mutation

IDH1/2 mutations which result in alternation in DNA methylation pattern are one of the most commonmethylation associated mutations in Acute myeloid leukaemia. IDH1/2 mutations frequently associated withhigher platelet level, normal cytogentics and NPM1 mutations. Here we analyzed IDH1/2 mutations in 200 newlydiagnosed unselected Indian adult AML patients and investigated their correlation with clinical, cytogeneticparameters along with cooperating NPM1 mutation. We detected 5.5% and 4% mutations in IDH1/2 genes,respectively. Except IDH2 c.515_516GG>AA mutation, all the other identified mutations were reported mutations.Similar to reported c.515G>A mutation, the novel c.515_516GG>AA mutation replaces 172nd arginine to lysinein the active site of the enzyme. Even though there was a preponderance of IDH1/2 mutations in NK-AML,cytogenetically abnormal patients also harboured IDH1/2 mutations. IDH1 mutations showed significant higherplatelet count and NPM1 mutations. IDH2 mutated patients displayed infrequent NPM1 mutations and lowerWBC count. All the NPM1 mutations in the IDH1/2 mutated cases showed type A mutation. The present datasuggest that IDH1/2 mutations are associated with normal cytogenetics and type A NPM1 mutations in adultIndian AML patients.     

IDH1 Overexpression Induced Chemotherapy Resistance and IDH1 Mutation Enhanced Chemotherapy Sensitivity in Glioma Cells in Vitro and in Vivo

Isocitrate dehydrogenase (IDH) is of great importance in cell metabolism and energy conversion. IDH mutationin glioma cells is reported to be associated with an increased overall survival. However, effects biological behaviorof therapy of gliomas are unclear. Here, we investigated the influence of wild-type and mutated IDH genes onglioma cell biological behavior and response to chemotherapy. Relevant mechanisms were further explored.We designed our study on the background of the IDHR132H mutation. Stable cell lines were constructed bytransfection. The CCK-8 method was used to assess cell proliferation, flow cytometry for the cell cycle andcell apoptosis, and the transwell method for cell invasion. Nude mouse models were employed to determinetumorigenesis and sensitivity to chemotherapy. Western blotting was used to detect relevant protein expressionlevels. We found that overexpression of wild IDH1 gene did not cause changes in the cell cycle, apoptosis andinvasion ability. However, it resulted in chemotherapy resistance to a high dose of temozolomide (TMZ) in vivoand in vitro. The IDH1 mutation caused cell cycle arrest in G1 stage and a reduction of proliferation and invasionability, while raising sensitivity to chemotherapy. This may provide an explanation for the better prognosis ofIDH1 mutated glioma patients and the relative worse prognosis of their wild-type IDH1 counterparts. We alsoexpect IDH1 mutations may be optimized as new targets to improve the prognosis of glioma patients.     

Clinicopathological Features and Prognosis of Indonesian Patients with Gliomas with IDH Mutation: Insights into Its Significance in a Southeast Asian Population

Background: Gliomas remain one of the most common primary brain tumors. Mutations in the isocitrate dehydrogenase (IDH) gene are associated with a distinct set of clinicopathological profiles. However, the distribution and significance of these mutations have never been studied in the Indonesian population. This study aimed to elucidate the association between IDH mutations and clinicopathological as well as prognostic profiles of Indonesian patients with gliomas. Methods: In total, 106 patients with gliomas were recruited from a tertiary academic medical center in Yogyakarta, Indonesia. Formalin-fixed paraffin-embedded and fresh tissue specimens were obtained and sectioned for hematoxylin-eosin staining and immunohistochemical examinations. Genomic DNA was isolated and analyzed for the presence of IDH mutations using standard polymerase chain reaction and nucleotide sequencing methods. Clinicopathological data were collected from medical records. Results: Although no IDH2 mutation was identified, IDH1 mutations were found in 23 (21.7%) of the patients. Patients with IDH1 mutations tended to have a history of smoking and a shorter interval between onset of symptoms and initial surgical interventions. Frontal lobe involvement, oligodendroglial histology, lower Ki67 expression, WHO grades II and III gliomas, and methylated O6-methylguanine-DNA methyltransferase (MGMT) promoters were significantly associated with the presence of IDH1 mutations. Compared with patients with IDH1-wild-type, patients with IDH1 mutation were observed to have a longer overall survival. Conclusions: IDH1 mutations are associated with certain clinicopathological and prognostic profiles in Indonesian patients with gliomas. This finding demonstrates the importance of identifying IDH mutations as part of the management of patients with glioma in Indonesia.     

Expression Profile Analysis of Zinc Transporters (ZIP4, ZIP9, ZIP11, ZnT9) in Gliomas and their Correlation with IDH1 Mutation Status

Background: Zinc transporters have been considered as essential regulators in many cancers; however, theirmechanisms remain unknown, especially in gliomas. Isocitrate dehydrogenase 1(IDH1) mutation is crucial toglioma. This study aimed to investigate whether zinc transporters are correlated with glioma grade and IDH1mutation status. Materials and Methods: IDH1 mutation status and mRNA expression of four zinc transporters(ZIP4, ZIP9, ZIP11, and ZnT9) were determined by subjecting a panel of 74 glioma tissue samples to quantitativereal-time PCR and pyrosequencing. The correlations between the expression levels of these zinc transportergenes and the grade of glioma, as well as IDH1 mutation status, were investigated. Results: Among the four zinctransporter genes, high ZIP4 expression and low ZIP11 expression were significantly associated with higher grade(grades III and IV) tumors compared with lower grade (grades I and II) counterparts (p<0.0001). However,only ZIP11 exhibited weak correlation with IDH1 mutation status (p=0.045). Samples with mutations in IDH1displayed higher ZIP11 expression than those without IDH1 mutations. Conclusions: This finding indicated thatzinc transporters may interact with IDH1 mutation by direct modulation or action in some shared pathwaysor genes to promote the development of glioma. Zinc transporters may play an important role in glioma. ZIP4and ZIP11 are promising molecular diagnostic markers and novel therapeutic targets. Nevertheless, the detailedbiological function of zinc transporters and the mechanism of the potential interaction between ZIP11 and IDH1mutation in gliomagenesis should be further investigated.     

IDH1、IDH2基因突变在肿瘤中的作用

异柠檬酸脱氢酶（IDH）是三羧酸循环中的一种关键酶,近年来在多种肿瘤中发现了频发的 IDH1、IDH2基因突变,这些突变特异性改变酶的催化活性,即直接催化α-酮戊二酸（α-KG）生成 R-2-羟戊二酸（R-2-HG）,竞争性抑制组蛋白和 DNA 去甲基酶等多种α-KG 依赖的双加氧酶,并可能由此促进肿瘤的发生发展,此外,IDH1、IDH2基因突变状态与肿瘤患者预后相关。IDH1、IDH2基因是一个潜在的肿瘤早期诊断、预后评估和靶向治疗的标志性基因。