星形细胞瘤中p53基因产物的表达

应用免疫组化方法，对２７例星形细胞瘤中的ｐ５３蛋白表达进行研究。结果表明：ｐ５３蛋白表达位于细胞核内，２７例星形细胞瘤中ｐ５３蛋白阳性检出率为７４．０７％，ｐ５３蛋白免疫反应强度与肿瘤分化程度有关，随肿瘤恶性度增高，ｐ５３蛋白表达增强。     

P21-ras、P53、Ki-67蛋白的表达与星形细胞瘤分化及预后的相关性研究

目的分析Ｐ２１－ｒａｓ、Ｐ５３、Ｋｉ－６７在星形细胞肿瘤中的表达,与肿瘤增生活性、分化和预后的关系。方法应用免疫组化ＬＳＡＢ法对６６例星形细胞瘤Ｐ２１－ｒａｓ、Ｐ５３、Ｋｉ－６７表达进行检测,对其中４７例有随访资料的肿瘤患者存活因素进行分析。结果Ｐ５３、Ｋｉ－６７的表达与肿瘤分级密切相关（Ｐ＜０．０１）。Ｐ５３、Ｋｉ－６７在肿瘤中的表达呈正相关（Ｐ＜０．０５）。Ｐ５３表达阳性,和Ｋｉ－６７表达指数高的肿瘤预后较差。Ｐ２１－ｒａｓ表达与肿瘤分化及预后未见显著差异。（Ｐ＞０．０５）。结论星形细胞瘤也存在Ｐ２１－ｒａｓ基因异常,Ｐ５３、Ｋｉ－６７能客观的反映肿瘤的增殖速度,分化和恶性程度,可以作为判断肿瘤预后的有用指标。     

星形细胞瘤中PTEN、Mdm2和p53表达的相关性研究

目的　探讨不同组织病理分级的星形细胞瘤中PTEN、Mdm2和p5 3的表达水平 ,并分析PTEN影响Mdm2和p5 3表达的信号转导机制。方法　采用免疫组织化学方法检测 6 8例星形细胞瘤标本中 ,PTEN、Mdm2和p5 3的表达水平。结果　星形细胞瘤中 ,PTEN、Mdm2和p5 3的表达水平分别为 5 4 .4 % (37/ 6 8)、4 1.2 % (2 8/ 6 8)和 4 5 .6 % (31/ 6 8)。PTEN阳性标本中 ,Mdm2的表达率 (2 4 .3% ,9/ 37)与PTEN阴性标本中该蛋白的表达率 (6 1.3% ,19/ 31)相比 ,差异有显著性 ,统计学分析显示 ,PTEN表达与Mdm2表达呈负相关 (P <0 .0 1)。Mdm2表达和p5 3表达一致 ,符合率为 6 6 .2 % (45 / 6 8) ,两者的表达密切相关 (P <0 .0 5 )。结论　PTEN、Mdm2和p5 3表达与星形细胞瘤的组织病理分级相关 ;抑癌基因PTEN可以下调癌基因Mdm2的表达水平 ;Mdm2和p5 3的表达存在一致性。     

PTEN,EGFR,p16在星形细胞瘤中的表达及意义

目的:探讨PTEN,EGFR,p16,Ki蛳67和p53在星形细胞瘤中的意义。方法:建立64例星形细胞瘤和10例脑组织共224个点的组织芯片,应用免疫组化S蛳P法。结果:1)星形细胞瘤Ⅱ级、Ⅲ级、Ⅳ级中PTEN,p16蛋白的表达明显低于Ⅰ级和正常脑组织;EGFR表达前者明显高于后者,差异有显著性(P<0.05)。2)PTEN,p16表达与组织学分级、Ki蛳67标记指数、p53负相关;EGFR表达与组织学分级、Ki蛳67标记指数、p53呈正相关,差异有显著性(P<0.01)。3)PTEN与EGFR蛋白表达显著负相关(P<0.01),但二者与p16无显著相关性(P>0.05)。结论:PTEN,EGFR,p16的表达失调可能与星形细胞瘤的发生发展及生物学行为有关。     

脑星形细胞瘤p53蛋白的表达及其意义

采用抗ｐ５３单克隆抗体ＰＡｂ２４０对５４例，其中复发者１６例的脑星形细胞组织中ｐ５３蛋白表达进行检测，并结合临床病理进行相关性研究。结果显示星形细胞瘤ｐ５３蛋白总的阳性表达率为２４．１％（１３／５４），Ⅰ、Ⅱ、Ⅲ～Ⅳ级组间的阳性表达率差异有显著性（Ｐ＜０．０１），复发组ｐ５３蛋白表达显著高于原发组（Ｐ＜０．０１），复发者ｐ５３蛋白阳性表达的患者预后不良（Ｐ＜０．０１），表明ｐ５３蛋白表达与肿瘤恶性度呈正相关，它可以作为肿瘤恶性度有价值的标志物，复发与原发星形细胞瘤的生物学特征不尽完全相同     

TP53、EGFR共突变对NSCLC治疗的影响及对预后预测作用的进展

摘 要：随着二代基因检测技术的发展,人们发现与单个基因突变相比,多个体细胞共突变已被证明与预后较差有关。在这些共突变中,TP53突变最常见,但被认为是不可用药的靶点。近年来对TP53突变的预测价值进行了深入研究,由于结果不一致,尚未达到临床应用。本篇综述通过对近几年国内外关于TP53抑癌基因与EGFR共突变对非小细胞肺癌（non-small cell lung cancer,NSCLC）治疗及预后的影响进行小结,为EGFR伴随TP53突变NSCLC的靶向治疗提供新的思路。     

TP53突变与胶质瘤恶性进展

背景与目的：WHOⅡ级的星形细胞瘤手术后在部分患者可能复发，而且，复发时多出现恶性程度增加。本研究探讨TP53蛋白质分子的表达与胶质瘤恶性进展之间的关系。方法：收集第一次手术时为星形细胞瘤（WHOⅡ级）的石蜡包埋标本53例份，其中10例复发时第二次手术肿瘤仍然为Ⅱ级（复发无进展组）；10例复发时肿瘤级别升高（Ⅲ级或Ⅳ级）（复发进展组）；另外13例在5年内没有复发（无复发组）。免疫组化检测TP53在肿瘤中的表达，并采用DNA测序法分析TP53蛋白阳性标本TP53外显子5、7、8的突变情况。结果：LTP 53阳性率为45．5％（15／33）。复发恶性进展组TP53高于无复发组和无进展组（P〈0．05）；TP53无进展组与无复发组之间差异无统计学意义。基因测序共在6例组织中发现7个（共4类）突变，其中1例同时存在2个突变。所有突变者都是恶性进展组病例。结论：TP53突变／蛋白质分子过表达可能是Ⅱ级星形胶质细胞瘤复发恶性进展的预示指标。     

FLI-1在星形细胞瘤组织中的表达及与预后的关系

摘 要：［目的］ 探讨FLI-1在星形细胞瘤手术患者肿瘤组织中的表达及其与患者预后的关系。［方法］ 选取104例星形细胞瘤手术患者作为研究对象,采用免疫组化技术分析患者肿瘤组织及癌旁组织的FLI-1表达水平,分析FLI-1表达水平与临床病理特征及预后的相关性,并分析星形细胞瘤患者的预后影响因素。［结果］ 星形细胞瘤组织中FLI-1高表达比例（74.0%）显著高于癌旁组织（11.5%）（P<0.001）。FLI-1表达水平与星形细胞瘤患者的WHO分级显著相关（P<0.001）。FLI-1低表达的星形细胞瘤患者中位生存期（35.3±5.6个月）和3年生存率（44.4%）均高于FLI-1高表达患者（8.9±2.1个月,13.0%;P均＜0.05）。Cox单因素和多因素分析结果均显示WHO分级及FLI-1表达水平是星形细胞瘤患者的预后影响因素（P＜0.05）。［结论］ 星形细胞瘤组织中FLI-1表达水平显著升高,且与患者预后相关,是一个潜在的预后指标。     

Mina53与CBX8在肝细胞肝癌中的表达及其与临床病理特征和预后的关系

目的探讨Mina53与CBX8在肝细胞肝癌中的表达,并分析两者与肝细胞肝癌患者临床病理特征及预后的关系。方法收集121例肝细胞肝癌患者术后切除标本制作组织芯片,采用免疫组织化学PV6000法检测Mina53与CBX8在肝细胞肝癌及相应癌旁相对正常组织中的表达,应用SPSS23.0软件对数据进行统计分析。结果 Mina53、CBX8在肝细胞肝癌中的表达水平高于癌旁相对正常组织(均P<0.001)。Mina53表达与肿瘤大小、被膜侵犯、脉管侵犯、病理分级、TNM分期有关(均P<0.05);CBX8表达与乙肝表面抗原(HBsAg)、肿瘤大小、被膜侵犯、TNM分期有关(均P<0.05)。肝细胞肝癌中Mina53与CBX8表达呈正相关(r=0.574,P<0.01)。Mina53与CBX8均高表达患者的OS和DFS较Mina53或CBX8高表达者和两者均低表达者更短(均P<0.001)。多因素分析显示,Mina53、CBX8的表达水平是肝细胞肝癌患者术后OS和DFS的独立预后影响因素(P<0.05)。结论 Mina53及CBX8在肝细胞肝癌组织中高表达,可能与...     

TP53 and EGFR Mutational Status in Thymoma: A Genetic Sequencing Study

Background and objective: Thymoma is a rare malignant tumor that usually with an indolent presentation, which was falsely assumed to be benign previously. The tumor suppressor P53 (TP53) and EGFR gene mutate most frequently in human cancers. We tried to investigate the presence of TP53 and EGFR mutations among thymoma patients referred to an Indonesian referral respiratory hospital and to discuss its potential role in thymoma management and prognosis. Material and methods: Surgically resected tumor tissues were collected from thymoma patients and then underwent genomic analysis. PCR was performed on the extracted Paraffinized  DNA to amplify exon 6 of TP53 and exons 18, 19, and 21 of EGFR. The evaluation of mutational status was done using direct sequencing and sequence analysis of purified PCR products. Results: Among 27 collected samples, TP53 exon 6 mutation, namely  missense mutation and nonsense mutation, was observed in two samples (7.4%). EGFR exon 18 mutation, namely E709K and nonsense mutation, was found in 2 samples (7.4%). An intronic mutation in EGFR exon 19 (3.7%) and exon 21 (3.7%) was observed in one sample. Conclusion: TP53 and EGFR mutations were not most frequent, so it seems that these genes are not involved in the pathogenesis of thymoma in Indonesian patients. Nevertheless, we found two samples with a significant mutation in p53 and EGFR genes, suggesting further research on thymoma prognostification and targeted therapy.     

骨肉瘤中PD-1和CTLA-4的表达与患者临床病理特征及预后的相关性

目的探讨PD-1和CTLA-4在骨肉瘤中的表达及其临床病理意义。方法收集2007—2016年南部战区总医院初诊初治骨肉瘤患者58例,运用免疫组织化学EnVision法检测PD-1、CTLA-4蛋白的表达。结果PD-1阳性31例(53.4%),阴性27例(46.6%);CTLA-4阳性19例(32.8%),阴性39例(67.2%);PD-1和CTLA-4双阳性12例(20.7%),双阴性20例(34.5%),单阳性26例(44.8%)。PD-1阳性与是否行新辅助化疗、肿瘤复发和转移有关,PD-1阳性患者无病生存期及总生存期更短(P<0.05);CTLA-4阳性与Ennecking分期较晚有一定关联(P=0.051);PD-1和CTLA-4双阳性表达较双阴性和单阳性患者术后复发和转移比例显著升高(P<0.05),且生存期更短(P<0.05)。结论PD-1和CTLA-4阳性表达的患者预后不良,双阳性患者的预后较差,可作为骨肉瘤免疫治疗的有效依据。     

IDH2 and TP53 mutations are correlated with gliomagenesis in a patient with Maffucci syndrome

We report on a 24‐year‐old woman who was diagnosed as having Maffucci syndrome with anaplastic astrocytoma. We analyzed the IDH1 and IDH2 mutations of enchondroma, hemangioma and anaplastic astrocytoma tissues and the same somatic mosaic mutation in IDH2 gene was identified in all these tissues. In addition, we identified additional mutation of the TP53 gene in anaplastic astrocytoma tissue but not in other benign tumors. This is the first report of the detection of an identical IDH2 mutation in multiple tissues and TP53 mutation in anaplastic astrocytoma in a patient with Maffucci syndrome. This case is unique and supports the IDH2‐dependent genetic pathway and second‐hit model for gliomagenesis.     

Concurrent TP53 mutations predict a poor prognosis of EGFR-mutant NSCLCs treated with TKIs: An updated systematic review and meta-analysis

The prognostic value of tumor protein P53 (TP53) mutation for tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant non-small-cell lung cancer (NSCLC) remains controversial. Therefore, the present meta-analysis was performed to investigate the potential association between the prognosis of TKI treatment for patients with advanced EGFR mutation-positive NSCLC and the presence or absence of concurrent TP53 mutations. In the present study, 24 eligible studies from the PubMed, Embase and Cochrane databases were identified by screening prior to inclusion. Data were extracted by two independent investigators and analyzed using STATA 14.0 software. Pooled odds ratios (ORs) with 95% confidence interval (CIs) were used to determine the association between objective response rates (ORRs) and TP53 mutations. In addition, differences in the incidence of TP53 mutations between patients with exon 21 L858R mutations and exon 19 deletions of EGFR were evaluated using this method. Pooled hazard ratios (HRs) with 95% CIs were used to calculate the prognostic value of TP53 mutations for progression-free survival (PFS) and overall survival (OS). No significant difference in the incidence of TP53 mutations was detected between the patients with exon 21 L858R mutation and those with exon 19 deletion (OR=0.91; 95% CI=0.65-1.27; P=0.568). However, the pooled results revealed that TP53 mutations were significantly associated with shorter PFS (HR=1.51; 95% CI=1.33-1.71; P<0.001) and OS (HR=1.64; 95% CI=1.33-2.02; P<0.001). By contrast, TP mutations were not associated with the ORR of EGFR-TKI treatment (OR=0.91; 95% CI=0.69-1.21; P=0.529). In conclusion, a worse prognosis for TKI treatment was observed in patients with EGFR-mutant NSCLCs and concurrent TP53 mutations, suggesting that TP53 mutations is associated with primary resistance to EGFR-TKIs.     

O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course

Epigenetic silencing of O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation can confer cancer cells with an increased sensitivity to alkylating chemotherapeutic agents and a higher susceptibility to TP53 transition mutations. The aim of our study was to assess the correlation of promoter methylation of the MGMT gene with TP53 mutations and the clinical characteristics of malignant astrocytomas. We analyzed the MGMT promoter methylation and TP53 mutations in 45 malignant astrocytomas (16 anaplastic astrocytomas and 29 glioblastomas multiforme) treated prospectively with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea, interferon-beta and radiation therapy, and evaluated their clinical usefulness. MGMT promoter methylation was found in 17 (38%) of the 45 newly diagnosed malignant astrocytomas. A clear trend existed between MGMT methylation and G:C to A:T transition mutations of TP53 (p = 0.0596). Patients with MGMT-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with MGMT-unmethylated tumors (p = 0.0393). TP53 mutation was not significantly associated with the clinical response (p = 0.1310). While neither MGMT methylation nor TP53 mutation had a significant effect on prognosis of the whole population, the presence of MGMT methylation emerged as a significant predictor of a longer survival when exclusively analyzing 29 patients with glioblastomas multiforme. These findings highlight the importance of MGMT methylation as a specific predictive factor for responsiveness to nitrosourea chemotherapy.     

Prognostic value of LAMP3 and TP53 overexpression in benign and malignant gastrointestinal tissues

Lysosomal associated membrane protein 3 (LAMP3) is a newly identified tumor-specific protein. It is a downstream target gene of tumor suppressor TP53 and its expression has been associated with hypoxia-induced metastasis and poor overall survival in cervical and breast cancers. However, little is known of LAMP3 protein expression in gastrointestinal cancer and its prognostic value. We determined protein expression of LAMP3 and TP53 in both gastric (n=750) and colorectal (n=479) tissues by immunohistochemistry analysis on tissue microarray (TMA), their expression was correlated with patients'' clinical parameters. LAMP3 and TP53 protein expression was significantly higher in cancerous tissues compared to normal and benign tissues. In both gastric and colorectal cancers, high LAMP3 protein expression (LAMP3+) was significantly associated with tumor stage (P=0.014 and P<0.001). No correlation between LAMP3 and TP53 expression was observed. Patients with high LAMP3 expression but not high TP53 expression had a poor overall survival (for gastric cancer P<0.001, CI: 1.762-4.567; for colorectal cancer P=0.036, CI: 1.062-5.980). Our data suggest that epithelial LAMP3 expression is an independent prognostic marker for gastrointestinal cancer.     

TP53突变对非小细胞肺癌表皮生长因子受体突变患者酪氨酸激酶抑制剂的治疗效果和预后影响

基因突变能够影响肺癌细胞对靶向药物的敏感性,导致个体化临床治疗效果出现差异。表皮生长因子受体(EGFR)的突变状态在内科药物治疗决策中具有重要意义。此外,其他并存的基因突变均可影响疾病的治疗效果和患者的远期临床预后。EGFR突变合并TP53突变是否可改变肺癌细胞对酪氨酸激酶抑制剂治疗的敏感性和对远期预后的影响一直受到人们的关注。目前在临床实践中,TP53的突变状态并不是临床治疗决策中的参考依据,因此需要进一步的证据阐明TP53(包括各亚型)突变状态对EGFR靶向治疗潜在获益的影响,以指导非小细胞肺癌的治疗。     

Comprehensive Analysis of TP53 and KEAP1 Mutations and Their Impact on Survival in Localized- and Advanced-Stage NSCLC

IntroductionTP53 and KEAP1 are frequently mutated in NSCLC, but their prognostic value is ambiguous, particularly in localized stage tumors.MethodsThis retrospective cohort study included a total of 6297 patients with NSCLC who were diagnosed between November 1998 and February 2020. The primary end point was overall survival. Patients were diagnosed in a central pathology laboratory as part of the Network Genomic Medicine collaboration, encompassing more than 300 lung cancer-treating oncology centers in Germany. All patients underwent molecular testing, including targeted next-generation panel sequencing and in situ hybridization.ResultsA total of 6297 patients with NSCLC were analyzed. In 1518 surgically treated patients (Union for International Cancer Control [UICC] I–IIIA), truncating TP53 mutations and KEAP1 mutations were independent negative prognostic markers in multivariable analysis (hazard ratio [HR]_{TP53truncating} = 1.43, 95% confidence interval [CI]: 1.07–1.91, p = 0.015; HR_KEAP1mut = 1.68, 95% CI:1.24–2.26, p = 0.001). Consistently, these mutations were associated with shorter disease-free survival. In 4779 patients with advanced-stage (UICC IIIB–IV) tumors, TP53 mutations did not predict outcome in univariable analysis. In contrast, KEAP1 mutations remained a negative prognostic factor (HR_KEAP1mut = 1.40, 95% CI: 1.23–1.61, p < 0.001) in patients with advanced-stage tumors. Furthermore, those with KEAP1-mutant tumors with co-occurring TP53 missense mutations had longer overall survival than those with KEAP1-mutant tumors with wild-type or truncating TP53 mutations.ConclusionsThis study found that TP53 and KEAP1 mutations were prognostic for localized and advanced-stage NSCLC. The increased relative hazard of harboring TP53 or KEAP1 mutations was comparable to an increase in one UICC stage. Our data suggest that molecular stratification on the basis of TP53 and KEAP1 mutation status should be implemented for localized and advanced-stage NSCLC to optimize and modify clinical decision-making.     

Alterations in p53, p21, and MIB-1 Labeling Index in Primary Human Astrocytomas Following Radiation Therapy

Summary Little is known about the cellular and genetic changes that occur in human astrocytomas following radiation therapy (RT). Experimental studies would suggest that early effects include induction of p53 and p21 expression, cell cycle arrest, and selection of tumor cells with molecular changes that correlate with radiation resistance. Unfortunately, tissue sampling of primary human astrocytomas closely following radiation therapy is uncommon, hindering comparative assessment of primary human tumors. Through local databases, we were able to collect eight cases in which tissue was resected within 8 weeks of RT because of bulky residual disease: two patients with grade II diffuse astrocytomas (LGA) and 6 patients with high-grade astrocytomas (HGA; 1 anaplastic astrocytoma, 5 glioblastomas). Routine histopathologic sections, MIB-1 labeling index (LI), p53 and p21 expression, and EGFR expression were compared between the pre- and post-RT samples. Only one tumor (52d post-RT) showed prominent radiation-induced histopathologic changes. p53 expression was detected in two tumors pre-RT and in six tumors post-RT. In the four tumors in which p53 expression was induced, the post-RT LI was lower in each case, and p21 expression had increased in 3/4 of these cases. No change in LI was detected in tumors in which p53 expression was unchanged. EGFR expression was not altered following RT. The results of this unique series document that some primary human astrocytomas increase expression of p53 and p21 and decrease proliferation in response to RT. However, the small size of the series argues for further studies of radiation induced molecular changes in primary human astrocytoma tissue.