IDH1基因突变在胶质瘤中的研究进展

胶质瘤是颅内最常见的恶性肿瘤,发病率逐年增高。越来越多的证据表明IDH1基因突变与胶质瘤密切相关。本文就近年来有关胶质瘤与IDH1基因突变的研究作一综述。IDH1基因编码胞浆内NADP依赖的异柠檬酸脱氢酶,后者能够对异柠檬酸进行催化生成α-酮戊二酸。在40%的胶质瘤中存在IDH1突变,在继发性胶质母细胞瘤中变异率最高。作为一种代谢的关键酶,IDH1突变后可以将α-KG转变成2-HG,后者具有促进细胞增殖和促进肿瘤发生的作用。而且,IDH1突变可以导致胶质瘤代谢和表观遗传学方面的改变。同时,IDH1突变可以通过增加HIF-1α水平及活性增加血管生成。目前在不同级别的胶质瘤当中,IDH1突变已经成为一个与预后密切相关的独立预测因素。对IDH1突变的研究有助于深入了解胶质瘤病因及干预措施的具体机制,有助于胶质瘤的分子水平分类和治疗。     

胶质瘤中的异柠檬酸脱氢酶突变

胶质母细胞瘤的基因组突变分析中发现的异柠檬酸脱氢酶（isocitrate dehydrogenase,IDH）突变对胶质瘤的认识具有突破性意义.随后,在胶质瘤中发现了IDH1的R132碱基和IDH2的R172碱基突变.IDH1突变较多的发生在WHOⅡ～Ⅲ级胶质瘤和继发胶质母细胞瘤中.这种突变改变了异柠檬酸脱氢酶的结构,从而使将异柠檬酸转化为α-酮戊二酸的能力丧失,而获得将α-酮戊二酸转化为D-2-羟基戊二酸这一新的酶活性.在临床中,IDH1和IDH2突变已经显示对胶质瘤患者有诊断和预后意义.同时,现今也发展了一些检测方法.     

异柠檬酸脱氢酶2突变或诱导机体产生肉瘤

<正>线粒体内依赖辅酶NADP+的异柠檬酸脱氢酶2(IDH2)在新陈代谢中起重要作用,IDH2催化异柠檬酸脱氢生成α-酮戊二酸(αKG),参与三羧酸循环。而当其发生突变时,IDH2则催化异柠檬酸生成2-羟戊二酸(2HG),并竞争性抑制αKG的DNA-组蛋白脱甲基酶,导致细胞分化功能受损。美国宾夕法尼亚大学Lu等人通过全组基因甲基化水平测定,发现IDH2突变通过甲基化DNA CpG岛产生致癌作用,但     

人脑胶质瘤中的IDH1/2突变

胶质母细胞瘤的基因组突变分析中发现的异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH1)突变对胶质瘤的认识具有突破性意义。随后,在胶质瘤中发现了IDH1的R132碱基和IDH2的R172碱基突变。IDH1突变较多的发生在WHOII-III级胶质瘤和继发胶质母细胞瘤中。这种突变改变了异柠檬酸脱氢酶的结构,从而使将异柠檬酸转化为a-酮戊二酸的能力丧失,而获得将a-酮戊二酸转化为2-羟基戊二酸这一新的酶活性。在临床中,IDH1和IDH2突变已经显示对胶质瘤患者有诊断和预后意义。同时,现今也发展了一些检测方法。     

异柠檬酸脱氢酶-1 突变及MGMT 甲基化在脑胶质瘤的诊断及治疗研究进展

异柠檬酸脱氢酶-1(Isocitrate dehydrogenase-1,IDH1)突变是脑胶质瘤中基因突变所导致的代谢物生成异常,突变型胶质瘤与普通型胶质瘤具有不同的分子生物学特征,并常与患者良好预后相关。MGMT(O6-methylguanine-DNA methyltransferase)启动子甲基化能够降低胶质瘤中DNA修复蛋白MGMT的表达,提高患者对化疗药物烷化剂治疗的敏感性。IDH1突变和MGMT启动子甲基化在胶质瘤的生长过程中存在关联,二者的联合检测对胶质瘤的预后及治疗方式具有一定的提示作用,在胶质瘤的分子病理学诊断方面具有很大的应用前景。目前IDH1突变和MGMT启动子甲基化的检测已逐渐应用于临床,但其诊断方式及治疗指导意义有待进一步研究探讨。本文就IDH1基因突变及MGMT启动子甲基化在胶质瘤诊断及治疗方面的研究进展进行综述。     

发现遏制肿瘤生长的有效代谢物

复旦大学生物医学研究院熊跃、管坤良教授所领导科研团队的研究成果—“神经胶质瘤衍生的IDH1突变显性抑制酶催化活性,激活HIFI”,初步探明了基因突变促进神经胶质瘤生长的分子机理,找到了遏制肿瘤生长的有效代谢物,为神经胶质瘤及其他肿瘤的治疗带来希望.IDH1基因突变在继发性神经胶质瘤中的突变频率高达75％以上,使得IDH1基因成为潜在的神经胶质瘤的诊断指针和靶向治疗目标。     

丙酮酸脱氢酶活性缺失与疾病发生的研究进展

丙酮酸脱氢酶系(pyruvate dehydrogenase complex,PDH_C)主要由丙酮酸脱氢酶(E1)、二氢硫辛酸乙酰转移酶(E2)、二氢硫辛酸脱氢酶(E3)和E3结合蛋白(E3BP)组成,绝大多数的丙酮酸脱氢酶系缺失都是由丙酮酸脱氢酶E1α亚基突变或者磷酸化引起,仅有少数突变发生在E2、E3和E3BP上。本文就PDHC的结构与功能,PDHA1基因突变和E1α磷酸化与其功能的关系,及在相关疾病包括肿瘤的发生、发展和转移中的分子机制的研究进展做一总结,以期对因E1α功能丧失引起的疾病的诊断与治疗有所借鉴意义。     

脑胶质瘤IDH1基因突变HRM检测方法的初步建立

在大多数弥漫性人脑胶质瘤中常伴随着异柠檬酸脱氢酶基因(isocitrate dehydrogenase gene)1(IDH1)的突变.有着此突变的胶质瘤患者在临床上有良好的预后效果,因此可以作为胶质瘤患者的分子标记.通过提取石蜡切片中的胶质瘤组织DNA,优化条件以初步建立IDH1基因突变高分辨率熔解曲线分析法(high resolution melting,HRM)检测方法.用HRM对胶质瘤石蜡包埋组织标本中IDH1基因检测突变,并用直接测序法对比,观察反应体系和反应条件的可行性.正交试验结果证明引物最适退火温度为53℃,20μL HRM反应体系中,0.6μmol/L引物,2.5 mmol/L Mg2+,60 ng DNA模板为最佳.HRM IDH1基因突变的结果和直接测序法结果一致,但灵敏度更高.说明此HRM方法简单,特异性强,准确可靠,可为IDH1突变检测的临床应用提供借鉴依据.     

α-酮戊二酸与动脉粥样硬化的关系研究进展

α-酮戊二酸(α-ketoglutarate,α-KG)是戊二酸带酮基的衍生物中的一种,是三羧酸循环中重要的代谢中间产物,通过异柠檬酸脱氢酶(IDH)催化异柠檬酸氧化脱羧和谷氨酸脱氢酶催化谷氨酸氧化脱氨产生,是连接细胞内碳-氮代谢的关键节点。动脉粥样硬化(atherosclerosis,As)是一种慢性进行性疾病,病因复杂,且容易引发多种心脑血管疾病。本文从血管内皮细胞功能、自噬、DNA甲基化修饰、能量代谢、血管衰老等方面探讨α-KG与As之间的关系及其调控机制。     

科研快讯

<正>《自然》:新型基因突变助力肝癌新型靶向疗法的开发近日,一项刊登在国际杂志Nature上的研究报告中,来自西奈山医疗中心等处的研究人员通过研究发现,肝脏细胞中的两种遗传突变或许会驱动肝内胆管细胞癌(iCCA的肿瘤形成,iCCA是第二大常见的肝癌。文章中,研究者表示他们发现了两种突变体蛋白质IDH1、IDH2存在和癌症之间关系,过去有研究发现,IDH的突变是iCCA病人最为常见的遗传差异,但是其如何促使癌症的发生却不得而知;在含有胆汁的肝脏中iCCA可以碰撞胆管样的结构,而胆汁则是食物消化所必需的,由于     

Recent advances in the study of Kaposi's sarcoma-associated herpesvirus replication and pathogenesis

It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus(KSHV; also known as human herpesvirus 8(HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.     

The structure, reproduction and taxonomy of Vidalia and Osmundaria (Rhodophyta, Rhodomelaceae)

Comprises species occurring mostly in subtidal habitats in tropical, subtropical and warm-temperate areas of the world. An analysis of the type species, V. spiralis (Sonder) Lamouroux ex J. Agardh, a species from Australia, establishes basic characters for distinguishing species in the genus. These characters are (1) branching patterns of thalli, (2) flat blades that may be spiralled on their axis, (3) width of the blade, (4) primary or secondary derivation of sterile and fertile branchlets and (5) position of sterile and fertile branchlets on the thalli. Application of the latter two characters provides an important basic method for separation of species into three major groups. Osmundaria , a genus known only in southern Australia, was studied in relation to Vidalia , and its separation from the Vidalia assemblage is not accepted. Species of Vidalia therefore are transferred to the older genus name, Osmundaria. Two new species, Osmundaria papenfussii and Osmundaria oliveae are described from Natal. Confusion in the usage of the epithet, Vidalia fimbriala Brown ex Turner has been clarified, and Vidalia gregaria Falkenberg, described as an epiphyte on Osmundaria pro/ifera Lamouroux, is revealed to be young branches of the host, Osmundaria prolifera.     

New or rare chromosome counts in Artemisia L. (Asteraceae, Anthemideae) and related genera from Kazakhstan

Fifteen chromosome counts of six Artemisia taxa and one species of each of the genera Brachanthemum, Hippolytia, Kaschgaria, Lepidolopsis and Turaniphytum are reported from Kazakhstan. Three of them are new reports, two are not consistent with previous counts and the remainder are confirmations of very scarce (one to four) earlier records. All the populations studied have the same basic chromosome number, x = 9, with ploidy levels ranging from 2x to 6x. Some correlations between ploidy level, morphological characters and distribution are noted.     

肝癌中HBV和HCV基因和抗原的分布及意义

采用原位分子杂交方法检测HCV RNA及HBV X基因;采用免疫组织化学方法研究HCV核心抗原,非结构区C33c抗原及HBxAg在肝细胞肝癌中的定位及分布.结果表明(1)HCV RNA、HBV X基因在肝细胞肝癌组织检出率分别为40%(55/136)和82%(112/136).HCV RNA定位于癌细胞的胞浆内,阳性细胞呈散在、灶状及弥漫分布三种形式;HBV X基因在肝癌细胞中的分布呈胞浆型、核型及核浆型,阳性细胞也呈上述三种分布形式;(2)HCV C33c抗原、核心抗原在肝细胞肝癌中的阳性率为81%(133/164)及86%(141/164).C33c抗原定位于癌细胞及肝细胞的胞浆内;核心抗原既定位于癌细胞核中,又可定位于胞浆中.C33c抗原阳性细胞以灶状分布为主;而核心抗原阳性细     

Selection with two alleles and complete dominance

For a plant selection model with frequency-independent viabilities, fertilities and selfing rates, it is shown that apart from global fixation, for certain parameter combinations a protected polymorphism and facultative fixation (either allele may become fixed according to initial frequencies) may both occur. Facultative fixation requires different selling rates for the dominant and recessive type. Protection of the polymorphism requires resource allocation for male and female function. In this connection the problem of purely genetically caused population extinction is discussed.
For general frequency dependence and regular segregation, the chances for establishment of a completely recessive gene are compared to those of a completely dominant gene. It is proven that the process of establishment of the recessive gene, despite a fitness advantage, may be considerably endangered by drift effects if random mating prevails. The recessive gene may reach the same effectivity in establishment as a dominant gene, only if the recessive homozygote mates exclusively with its own type during the period of establishment.