MGMT基因启动子甲基化与MGMT蛋白和NF-κB在脑胶质瘤的表达及意义

目的 探讨MGMT和NF-κB在脑胶质瘤中的表达及两者的相关性和MGMT基因启动子甲基化与其蛋白表达的相关性分析.方法 采用免疫组化EnVision法检测MGMT和NF-κB在42例不同级别脑胶质瘤石蜡标本中的表达,运用MSP方法检测MGMT基因启动子甲基化状况.结果 （1）MGMT在低级别组胶质瘤中的表达率为73.7％;在高级别组中其表达率为21.7％.（2） NF-κB在低级别组胶质瘤中的表达率为52.6％,在高级别组中的表达率为60.9％.（3）42例胶质瘤中MGMT基因启动子甲基化发生率为50％,其中MGMT蛋白阳性的胶质瘤,启动子甲基化发生率为26.3％;MGMT蛋白表达阴性的胶质瘤,启动子甲基化发生率为69.6％;MGMT蛋白表达阳性率与其基因启动子甲基化呈负相关.（4）MGMT与NF-κB两者表达无相关性.结论 MGMT蛋白表达随胶质瘤的级别增高而下降,NF-κB与MGMT与胶质瘤级别无相关性.     

智能影像预测高级别脑胶质瘤MGMT启动子甲基化状态的研究进展

胶质瘤是颅内最常见的原发性恶性肿瘤,具有高度异质性,即使组织学分级相同,有时预后也具有显著差异,而基因分型则可以从本质上更好地阐述肿瘤的生物学行为,其中O⁶-甲基鸟嘌呤甲基转移酶(O⁶-methylguanine-DNA methyltransferase,MGMT)与高级别脑胶质瘤(high-grade glioma,HGGs)的预后和治疗决策紧密相关。它是一种关键的DNA修复酶,不仅与脑胶质瘤的发生发展相关,还与烷化剂化疗的敏感性以及放疗反应相关。而MGMT启动子甲基化会沉默MGMT的转录表达,是MGMT表达减少的重要机制。近年来随着科学技术的飞速进步,放射学也逐渐向人工智能的方向发展,本文对智能影像对高级别脑胶质瘤MGMT启动子甲基化状态的预测性能进行了综述。     

MRI征象及表观弥散系数预测高级别胶质瘤O6-甲基鸟嘌呤DNA甲基转移酶启动子甲基化

目的 观察术前根据MRI征象及表观弥散系数（ADC）预测高级别胶质瘤（HGG）O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）启动子甲基化状态的价值。方法 回顾性分析85例经病理证实HGG患者术前头部MRI,71例各扫描序列图像完整、14例未接受弥散加权成像;其中58例MGMT启动子甲基化（+）、27例（-）。比较MGMT启动子不同甲基化状态下HGG的MRI定性指标（肿瘤部位、坏死/囊变、出血、瘤脑界面、强化程度）和定量指标[肿瘤最大径、水肿最大径、囊变最大径、最大ADC值（ADC_Max）、平均ADC值（ADC_Mean）、最小ADC值（ADC_Min）及相对ADC值（rADC）]的差异;绘制差异有统计学意义的定量指标预测HGG MGMT启动子甲基化的受试者工作特征（ROC）曲线,分析其诊断效能。结果 MGMT启动子甲基化（+）HGG瘤脑界面多模糊（39/58,P<0.05）;左侧颞叶HGG更易出现MGMT启动子甲基化（15/24,P<0.05）;不同MGMT启动子甲基化状态HGG其余MRI定性指标差异均无统计学意义（P均>0.05）。MGMT启动子甲基化HGG的ADC_Min、ADC_Mean及rADC[（0.98±0.25）s/mm²、（1.06±0.24）s/mm²、1.39±0.31]均高于启动子甲基化（-）者[（0.84±0.18）s/mm²、（0.92±0.18）s/mm²、1.19±0.30,P均<0.05]。ADC_Min截断值取0.88 s/mm²时,其预测MGMT启动子甲基化的敏感度和特异度分别为76.00%和71.40%;ADC_Mean截断值取0.98 s/mm²时,敏感度和特异度分别为72.00%和71.40%;rADC截断值取1.24时,敏感度和特异度分别为74.00%和71.40%。结论 术前MRI征象及ADC对于评价HGG MGMT启动子甲基化有一定价值。     

MRI不同影像组学模型预测胶质瘤MGMT启动子甲基化状态的研究

目的 探讨MRI的不同影像组学模型预测术前脑胶质瘤O6-甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyltransferase,MGMT)启动子甲基化状态的效能.材料与方法 回顾性分析经手术病理证实的114例大脑胶质瘤患者的MRI影像资料,包括T1WI、T2WI、ADC及T1WI增强...     

多模态磁共振技术预测脑胶质瘤MGMT启动子甲基化状态的研究进展

胶质瘤是最常见的原发性中枢神经系统恶性肿瘤。O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化是胶质瘤一个重要的分子特征,与烷化剂化疗敏感性、预后、风险分层、肿瘤复发等密切相关。当前仅使用手术标本通过基因检测分析来确定MGMT启动子甲基化状态,这一过程有局限性。MRI是目前应用最广泛的脑肿瘤非侵入性检查方法,近年来已有多种先进磁共振成像技术被用于术前无创性评估MGMT甲基化状态,这将有助于预测治疗反应和预后。本文就近几年化学交换饱和转移成像和酰胺质子转移成像、灌注加权成像（动态磁敏感对比增强成像、动态对比增强灌注成像、动脉自旋标记、基于流入的血管空间占位）、扩散成像（扩散张量成像、扩散峰度成像、体素内不相干运动、限制光谱成像）、磁敏感加权成像、波谱成像等磁共振成像技术预测MGMT甲基化状态的研究进展及MGMT甲基化临床意义进行综述,以期为患者个体化治疗方案的制定提供术前依据。      

基于T1WI增强的MR纹理分析评价胶质母细胞瘤MGMT启动子甲基化的研究

目的 本研究主要是分析O⁶-甲基鸟嘌呤-DNA甲基转移酶(MGMT)启动子甲基化状态与胶质母细胞瘤(GBM)磁共振纹理特征的相关性。方法 收集经本院病理诊断为GBM的患者128例，所有患者术前均行磁共振平扫及增强检查。利用3D Slicer软件提取4方面磁共振纹理特征，包括一阶数据、形态和形状、纹理：灰度共生矩阵、纹理：灰度运行长度矩阵。采用χ²检验分析MGMT启动子甲基化与GBM磁共振特征的关系；采用独立样本t检验以及Mann-Whitney U检验，分析MGMT启动子甲基化与磁共振纹理特征的关系。结果 MGMT启动子甲基化GBM与MGMT启动子未甲基化GBM的磁共振纹理特征相比较，有7种磁共振纹理特征差异显著(P<0.05)，分别是能量(P=0.033)、熵(P=0.032)、一致性(P=0.030)、自相关(P=0.035)、方差：灰度共生矩阵(P=0.031)、灰度不均匀性(P=0.029)、群集阴影(P=0.032)。结论 MGMT启动子甲基化GBM与MGMT启动子未甲基化GBM的磁共振纹理特征相比较，有7种磁共振纹理特征可以...     

联合检测粪便MGMT基因甲基化和隐血在结直肠癌诊断中的价值

目的探讨粪便O6-甲基鸟嘌呤-DNA甲基转移酶基因(MGMT)甲基化和粪便隐血试验(FOBT)联合检测在结直肠癌(CRC)诊断中的价值。方法用甲基化特异性PCR(MSP)及FOBT对56例CRC患者和34例体检健康者进行粪便MGMT基因启动子甲基化联合检测,分析MGMT基因启动子甲基化和FOBT与CRC临床病理特征的关系。结果 CRC患者粪便MGMT基因启动子甲基化率为33.9%,体检健康者为2.9%;联合FOBT检测诊断CRC敏感性为55.4%,明显高于单独MGMT基因甲基化的33.9%(χ2=14.674,P<0.01)和单独FOBT的33.4%(χ2=14.322,P<0.01)。MGMT基因甲基化与CRC患者的肿瘤部位、肿瘤大小、分化程度、Dukes分期均无相关性(P>0.05)。结论联合检测粪便MGMT基因启动子甲基化及隐血可提高CRC的诊断效率,有望成为CRC的非侵入性筛查方法。     

人脑胶质瘤组织中耐药相关基因MGMT、TopoⅡ的表达分析

目的 探究人脑胶质瘤组织中耐药相关基因O~6-甲基鸟嘌呤-DNA-甲基转移酶(MGMT)、DNA拓扑异构酶Ⅱ(TopoⅡ)的表达及意义。方法 采用免疫组化方法检测96例脑胶质瘤组织及30例正常脑组织MGMT及TopoⅡ的表达,比较不同组织基因表达差异,分析脑胶质瘤组织基因表达与临床资料及预后的关系。结果 脑胶质瘤组织中,MGMT及TopoⅡ表达阳性率分别为57.29%及36.45%;正常脑组织MGMT及TopoⅡ基因表达阳性率分别为6.33%及3.33%;差异有统计学意义(P0.05);TopoⅡ表达阳性率随肿瘤恶性程度增加而增加(P0.05);入组脑胶质瘤病例中79人获得随访,随访时间为3～32个月,MGMT及TopoⅡ表达阴性患者生存时间均长于表达阳性患者,差异有统计学意义(P0.05)。结论 人脑胶质瘤组织中MGMT及TopoⅡ有较高的阳性表达率,其中TopoⅡ表达与脑胶质瘤恶性程度相关,两者表达情况均与患者预后相关。     

IVIM在预测高级别脑胶质瘤MGMT启动子甲基化状态的应用价值

目的研究体素内不相干运动(intravoxel incoherent motion,IVIM)在预测高级别脑胶质瘤O~6-甲基鸟嘌呤-DNA甲基转移酶(O~6-methylguanine-DNA methyltransferase,MGMT)启动子甲基化状态的应用价值。材料与方法收集经病理证实的34例高级别脑胶质瘤患者,其中包括WHOⅢ级19例,Ⅳ级15例,术前均行颅脑常规磁共振成像(magnetic resonance imaging,MRI)扫描及IVIM扫描,测量肿瘤实质区域及对侧正常脑组织区域,获得真扩散系数(true diffusion coefficient,D)、灌注相关扩散系数(perfusion related diffusion coefficient,D*)、灌注分数(perfusion fraction,f),将肿瘤实质区测量值除以对侧正常脑实质区,得到校正后参数值:相对D (relative D)、相对D*(relative D*)、相对f (relative f),应用两独立样本t检验分析MGMT启动子甲基化组与非甲基化组间校正参数的差异,并绘制受试者工作特征(receiver operating characteristic,ROC)曲线计算阈值、敏感性及特异性。结果高级别脑胶质瘤MGMT启动子甲基化组中rD、rf值高于非甲基化组,rD*值低于非甲基化组,差异均有统计学意义(P0.05)。rD、rD*、rf值的ROC曲线下面积分别为:0.856、0.814、0.719;阈值分别为:1.703、1.058、1.756;敏感度分别为:84.2%、89.5%、63.2%;特异度分别为:73.3%、60.0%、93.3%。结论 IVIM能无创地评估高级别脑胶质瘤MGMT启动子甲基化状态,其中rD*的灵敏度较高,有助于指导患者的个性化诊治方案以及对预后的评估。     

甲基化敏感性高分辨率熔解曲线检测结直肠癌组织及外周血MGMT基因甲基化

目的用甲基化敏感性高分辨率熔解曲线法(MS-HRM)定量检测结直肠癌组织及外周血中MGMT基因甲基化水平,并结合结直肠癌病理参数分析探讨MGMT基因甲基化的临床意义。方法以33例结直肠癌组织和配对的正常黏膜组织以及其中16例患者的外周血为研究对象,用MS-HRM进行MGMT基因甲基化检测,分析MGMT基因甲基化与结直肠癌临床病理特征的关系和MS-HRM的方法特点。结果 MS-HRM从33例结直肠癌患者的癌组织中检测到12例(36.4%)MGMT基因启动子不同程度的甲基化(甲基化5%1例,5%~10%3例,10%~25%3例,25%~50%2例,50%~75%3例),对应的正常结直肠组织中仅检测到甲基化5%1例(3.0%)。16例外周血中检测到甲基化小于5%3例(18.8%)。MGMT基因甲基化与患者的年龄、性别、肿瘤部位无相关性(P0.05),但与结直肠癌的病理分期和分化程度的相关性有统计学意义(P0.05)。结论 MS-HRM可定量检测结直肠癌MGMT甲基化水平。MGMT基因甲基化与结直肠癌的进展评估有关。     

Alkylpurine-DNA-N-glycosylase confers resistance to temozolomide in xenograft models of glioblastoma multiforme and is associated with poor survival in patients

Glioblastoma multiforme (GBM) is the most common and lethal of all gliomas. The current standard of care includes surgery followed by concomitant radiation and chemotherapy with the DNA alkylating agent temozolomide (TMZ). O⁶-methylguanine–DNA methyltransferase (MGMT) repairs the most cytotoxic of lesions generated by TMZ, O⁶-methylguanine. Methylation of the MGMT promoter in GBM correlates with increased therapeutic sensitivity to alkylating agent therapy. However, several aspects of TMZ sensitivity are not explained by MGMT promoter methylation. Here, we investigated our hypothesis that the base excision repair enzyme alkylpurine–DNA–N-glycosylase (APNG), which repairs the cytotoxic lesions N³-methyladenine and N⁷-methylguanine, may contribute to TMZ resistance. Silencing of APNG in established and primary TMZ-resistant GBM cell lines endogenously expressing MGMT and APNG attenuated repair of TMZ-induced DNA damage and enhanced apoptosis. Reintroducing expression of APNG in TMZ-sensitive GBM lines conferred resistance to TMZ in vitro and in orthotopic xenograft mouse models. In addition, resistance was enhanced with coexpression of MGMT. Evaluation of APNG protein levels in several clinical datasets demonstrated that in patients, high nuclear APNG expression correlated with poorer overall survival compared with patients lacking APNG expression. Loss of APNG expression in a subset of patients was also associated with increased APNG promoter methylation. Collectively, our data demonstrate that APNG contributes to TMZ resistance in GBM and may be useful in the diagnosis and treatment of the disease.     

Detailed methylation patterns and protein expression profiles of MGMT in colorectal carcinoma surgical margins

OBJECTIVES: Molecular margin analysis is considered more sensitive in detecting preneoplastic lesions and residual cancer cells than conventional histological margin examination. Hence, we examined MGMT expression profile and methylation status in histologically negative margins of colorectal cancer patients. DESIGN AND METHODS: This study included 24 colorectal tumor tissues and corresponding negative surgical margin tissues. MGMT promoter methylation patterns were analyzed by using methylation-specific oligonucleotide microarray. In addition, MGMT protein expression was analyzed by immunohistochemistry. MGMT clinical significance was evaluated together with other well-known clinicopathological factors. RESULTS: Extensive MGMT promoter methylation was observed in tumor tissues; a moderate methylation level was found in surgical margin tissues and little or no methylation was observed in the normal control. There was a trend towards longer overall survival for those patients with negative MGMT immunostaining in surgical margins. CONCLUSIONS: MGMT expression negative in surgical margin tissues indicates longer overall survival for colorectal tumor patients.     

Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas

Promoter methylation of O6-methylguanine DNA methyltransferase (MGMT) is associated with a favorable prognosis in glioblastoma multiforme (GBM) and has been hypothesized to occur early in tumor transformation of glial cells. Thus, a possible link exists between the site of malignant transformation and MGMT promoter methylation status. Using the Analysis of Differential Involvement (ADIFFI) statistical mapping technique in a total of 358 patients with GBM, we demonstrate that human de novo GBMs occur in a high frequency contiguous with the posterior subventricular zone (SVZ); MGMT promoter methylated GBMs are lateralized to the left hemisphere, while MGMT unmethylated GBMs are lateralized to the right hemisphere; and tumors near the left temporal lobe have a significantly longer overall survival compared with tumors occurring elsewhere, independent of treatment or MGMT methylation status.     

NSCLC组织中MGMT过甲基化状况与临床病理特征的关系探讨

目的探讨非小细胞肺癌（NSCLC）组织中DNA修复酶O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）过甲基化状况与临床病理特征的关系。方法以2006年3月到2009年7月在河南省胸科医院胸外科手术治疗的77例NSCLC患者作为研究对象,另外选取20例肺良性病变患者作为对照组,采用甲基化特异性PCR（MSP）检测两组病例肺部病变组织中MGMT的甲基化状况。结果研究组有26例出现MGMT基因甲基化,发生率为33.8%,对照组无1例出现MGMT基因甲基化,组间比较差异有统计学意义（P〈0.05）;NSCLC中MGMT过甲基化状态与有吸烟史、有淋巴结转移、TNM分期为Ⅲ期和分化程度为低分化有关,与患者年龄、性别和组织学类型无关。结论 NSCLC组织中的MGMT过甲基化状况可能与肺癌的发生、发展相关。     

Role of MGMT as biomarker in colorectal cancer

O⁶-methylguanine DNA methyltransferase (MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients.