MGMT蛋白的表达与乳腺癌预后关系初探

目的:探讨MGMT蛋白在乳腺癌中的表达及其与乳腺癌预后的关系。方法:应用免疫组化法检测135例乳腺癌患者MGMT蛋白的表达,并探讨其与乳腺癌临床特征及预后的关系。结果:135例乳腺癌中MGMT蛋白总阳性率为84.4 %(114/135),但存在异质性。MGMT蛋白的阳性表达与患者年龄、月经状态、原发肿瘤大小、淋巴结转移情况及肿瘤的临床分期无明显相关性(P>0.05),与生存期无明显相关性(P>0.05),但与ER状况相关(P<0.025)。结论:MGMT蛋白的表达不能作为乳腺癌的一个预后指标。     

MGMT表达与非小细胞肺癌化疗疗效和预后关系的研究

目的　研究MGMT在非小细胞肺癌 (NSCLC)组织中的表达情况及其与NSCLC患者化疗疗效和预后的关系。方法　应用免疫组化S P法检测正常肺组织及肿瘤组织中的MGMT表达。将 12 8例NSCLC组织分为Mer-组 (MGMT表达阴性 )和Mer+ 组 (MGMT表达阳性 )。结果　 12 8例NSCLC中阳性表达率为 47.66% ( 61/ 12 8) ,而 10例正常肺组织中未见MGMT表达。MGMT表达与肺癌患者性别、年龄、肿瘤分期、淋巴结转移、组织类型等临床生理病理特征均无明显关系。Mer-组术后平均生存期及生存率均较Mer+ 组明显延长 (P <0 .0 1,P <0 .0 5 )。 45例可评价疗效的病例中 ,Mer-组总的化疗有效率为 42 .86% ( 9/2 1) ,Mer+ 组为 4.17% ( 1/ 2 4) (P <0 .0 0 1) ;Mer-组生存期和生存率明显高于Mer+ 组 (P <0 .0 1,P <0 .0 5 )。结论　MGMT表达水平可以作为临床预测NSCLC患者化疗疗效和预后的有意义的指标。     

甲醛对小鼠脏器MGMT的影响

目的　研究甲醛对小鼠脏器O6 -甲基鸟嘌呤 -DNA甲基转移酶 (MGMT )表达的影响。方法　选择健康昆明小鼠 40只 ,随机分为 4组 :甲醛低剂量组 (2 5mg/m3)、中剂量组 (5mg/m3)、高剂量组 (10mg/m3)、对照组 (无甲醛暴露 ) ,每组 10只。除阴性对照组外 ,其余 3组每日吸入甲醛 1次 ,每次 4h ,连续 9周。应用链霉亲和素生物素-过氧化物酶 (SABC)免疫组化法对小鼠脑、肺、肝及肾组织中MGMT进行检测。结果　 3个染毒组小鼠肝和肺组织中MGMT表达降低 ,与对照组比较具有显著性差异 (P <0 0 5或P <0 0 1) ;脑和肾组织MGMT表达各组之间无显著性差异 (P >0 0 5)。结论　甲醛对小鼠肝和肺组织MGMT表达可能具有抑制作用     

卵巢癌组织中MGMT表达意义

目的探讨6-氧-甲基鸟嘌呤-DNA甲基转移酶（MGMT）在卵巢癌中的表达及临床意义.方法应用免疫组化（SP）法对60例卵巢癌及癌旁正常组织中MGMT的表达进行检测.结果60例卵巢癌组织中MGMT的表达率为46.7%,癌旁正常组织MGMT的表达率为100%（P＜0.05）.MGMT的表达与卵巢癌的组织学类型和临床分期无关（P＞0.05）,但与卵巢癌的病理分级有关（P＜0.05）.结论卵巢癌组织中存在MGMT的表达缺失,MGMT的功能失活可能是卵巢癌发生的重要机制之一.     

Biomarker-guided implementation of the old drug temozolomide as a novel treatment option for patients with metastatic colorectal cancer

Temozolomide is an oral alkylating agent used for treating several cancers including glioblastoma and melanoma. Promising, albeit limited, activity and efficacy of temozolomide have been reported in pretreated patients with metastatic colorectal cancer bearing MGMT promoter methylation. MGMT silencing and proficiency of the mismatch repair system were considered the major predictive biomarkers of sensitivity to temozolomide. Refinement of established biomarkers and integration with those related to alteration in specific DNA-damage response pathways such as base excision repair are promising strategies for selecting metastatic colorectal patients to this old drug with several potential novel applications. Then, mounting preclinical and clinical observations have linked acquired resistance to temozolomide to emergence of alterations in the mismatch repair system. Whilst accounting for tumor cells capability of escaping apoptosis when exposed to temozolomide, inactivation of key mismatch-repair proteins will ultimately lead to increasing tumor mutational burden. This drug-induced mismatch deficient-like phenotype is being exploited in proof-of-concept trials combining temozolomide and immune checkpoint inhibitors in metastatic colorectal cancer.     

Does increase in DNA repair allow “Tolerance‐to‐Insult” in chemical carcinogenesis? Skin tumor experiments with MGMT‐overexpressing mice

Several genotoxicity endpoints have been evaluated to define nonlinear dose‐responses for S_N1 and S_N2 alkylating genotoxicants. Dose‐response studies acknowledging the process of multistage tumorigenesis are important; however, data pertaining nonlinearity are not yet available. In this communication, the role of DNA repair in the dose‐response relationship for benign papillomas was examined using the two‐stage skin carcinogenesis protocol. The data obtained with O⁶‐methylguanine‐DNA methyltransferase (MGMT) overexpressing mice in which papillomas were induced by a single topical treatment with N‐methyl‐N‐nitrosourea (MNU) followed by promotion with 12‐O‐tetradecanoylphorbol‐13‐acetate are reported. As MGMT efficiently protects cells from mutations by repairing O⁶‐methylguanine, a miscoding lesion induced by MNU, the question whether MGMT is able to nullify carcinogenic lesions to an extent where they would be considered nonhazardous has been addressed. It is shown here that MGMT overexpression significantly protects against, but does not completely nullify, the effect of MNU in tumor initiation. The possible mechanisms involved have also been discussed. Environ. Mol. Mutagen. 55:145–150, 2014. © 2013 Wiley Periodicals, Inc.     

Analysis of K-<Emphasis Type="Italic">ras</Emphasis> Codon 12 Mutation in Flat and Nodular Variants of Serrated Adenoma in the Colon

PURPOSE: The developmental process of serrated adenomas is obscure, and the importance of genetic alterations has not been elucidated clearly. The possibility that the developmental process and genetic alterations of serrated adenomas could differ from those of ordinary tubular adenomas was explored in this work. METHODS: Serrated adenomas were obtained by endoscopic resection (n = 57) and divided into two groups: flat (n = 10) and nodular (n = 47). Mutation of the K-ras gene was analyzed by enriched polymerase chain reaction–enzyme-linked mini-sequence assay, which can detect not only the presence of a mutation but also the mutation type of K-ras codon 12 with high sensitivity. Methylation-specific polymerase chain reaction was performed with specific primers for the DNA repair gene O6-methylguanine-DNA methyltransferase. RESULTS: Serrated adenomas located in the rectum were more likely to have a K-ras mutation (9/12, 75 percent), whereas serrated adenomas of the flat type were less likely to have one (1/10, 10 percent). Furthermore, nodular serrated adenomas that occurred in the rectum possessed a high frequency of K-ras gene codon 12 point mutation (8/10, 80 percent) despite an overall frequency of 46.8 percent (22/47). A mutation of the K-ras codon 12 gene was detected in 23 (40.4 percent) of 57 serrated adenomas. Three types of point mutations of codon 12 were detected, with the mutation of GAT being observed most frequently. CONCLUSIONS: This study shows that development of nodular serrated adenomas may depend on the mutation of the K-ras codon 12 gene, whereas development of flat serrated adenomas may not. Additionally, serrated adenomas that occur in the rectum are closely related to the mutation of the K-ras codon 12 gene. K-ras mutations in serrated adenomas may be unaffected by the epigenetic silencing of O6-methylguanine-DNA methyltransferase by promoter hypermethylation.     

Effect of Alcohol Drinking on Gene Expression of Hepatic O6-Methylguanine DNA Methyltransferase in Chronic Liver Diseases

O⁶-methylguanine DNA methyltransferase (MGMT) is a repair protein that transfers methyl groups from O⁶-methylguanine to a cysteine acceptor in its own molecule, and restores DNA to its undamaged state. If left unrepaired, O⁶-methylguanine can pair with either a thymine or a cytosine, causing a C-G to T-A transition, which is considered to be one of the molecular mechanisms of both mutagenesis and carcinogenesis. The expression of MGMT mRNA in liver tissue was quantitatively assessed by the competitive reverse transcrip-tion-polymerase chain reaction method in patients with chronic liver diseases with or without alcohol drinking. MGMT mRNA expression was 1.4 ± 0.9 pg/μg RNA in control livers. Its expression in chronic hepatitis was 3.8 ± 0.7 in alcoholics and 2.7 ± 0.8 in nonalcoholics, which were not statistically different. MGMT mRNA expression in liver cirrhosis was significantly low, compared with that in chronic hepatitis, and 0.8 ± 0.3 in alcoholics and 0.5 ± 0.1 in nonalcoholics, which also were not significantly different. The present study shows that MGMT mRNA was not decreased in patients with chronic liver diseases with alcohol drinking, compared with those without alcohol drinking.