p53基因突变与大肠癌预后的关系

抑癌基因p53是迄今发现与人类肿瘤相关性最高的基因，p53基因与人类50％的肿瘤有关。大肠癌是人类常见的恶性肿瘤之一，而p53基因与大肠癌发生密切相关。     

p53基因突变和肿瘤标志物对大肠癌患者预后的影响

进一步了解肿瘤标志物与基因检测在判断结直肠肿瘤患者预后中的价值，我们选用与大肠肿瘤关系甚密的ｐ５３基因，结合术前大肠相关抗原ＣＥＡ，ＣＡ１９－９的检测，对大肠癌患者的预后作一初步评价１材料和方法１．１材料１９９６－０３／１９９７－０６，对５４例结直肠癌患者手术切除的标本，选用ＰＣＲ－ＳＳＣＰ法行ｐ５３基因第５～８外显子检测５４例患者术前取血检测大肠相关抗原血清ＣＥＡ，ＣＡ１９－９水平，术后均行密切随访１．２方法ＣＡ１９－９测定采用法国ＣＩＳ公司的单克隆抗体ＣＡ１９－９ＩＲＭＡ法药盒进行检测，正常…     

p53基因突变及p53,APC基因缺失与胃癌关系的研究

为明确ｐ５３基因突变，缺失，ＡＰＣ基因缺失在胃癌发病机制中的作用，应用ＰＣＲ－ＳＳＣＰ方法对抑癌基因ｐ５３第４，５，６，７，８外显子，第６内含子在８７例胃癌及癌前病变中的突变规律以及ＰＣＲ－ＲＦＬＰ方法对ｐ５３基因第４外显子，第６内含子，ＡＰＣ基因在２５对胃癌及癌旁组织的杂合缺失规律进行了探讨，结果发同，ｐ５３突变率在肠化，不典型增生，胃癌分别为３７．５％（３／８），４２．１％（８／１９），５３．     

原发性胃癌p53基因突变

目的 p53基因是当前抑癌基因研究中的热点之一。迄今,有关 p53基因异常与胃癌临床病理学参数如大体类型、临床分期、组织分化程度,浸润深度及淋巴结转移之间的关系尚无定论。Tumura 报告p53基因改变主要发生于异倍体瘤,国内尚无报道。本实验目的主要是分析中国人原发性胃癌 p53基因突变与这些病理参数,包括 DNA 倍体之间的关系。方法用聚合酶链式反应—单构象多态分析(PCR—SSCP)技术对20例原发性胃癌 p53基因外显子5—8突变进行检测。结果 8例(40%)发生了突变,其中2例发生在外显子7,4例发生在外显子8。0至Ⅲ期均有突变存在。66.7%(6/9)的异倍体瘤检测到了p53突变,而二倍体瘤中只有18.2%(2/11)发生了 p53突变。结论 p53基因突变与胃癌临床病理参数如大体类型、分期、组织分化程度、浸润深度及淋巴结转移之间无明显关系,而与胃癌 DNA 倍体改变有关。     

p53基因突变及p53、APC基因缺失与胃癌关系的研究

为明确ｐ５３基因突变、缺失，ＡＰＣ基因缺失在胃癌发病机制中的作用，应用ＰＣＲ－ＳＳＣＰ方法对抑癌基因ｐ５３第４、５、６、７、８外显子、第６内含子在８７例胃癌及癌前病变中的突变规律以及ＰＣＲ－ＲＦＬＰ方法对ｐ５３基因第４外显子、第６内含子、ＡＰＣ基因在２５对胃癌及癌旁组织中的杂合缺失规律进行了探讨。结果发现，ｐ５３突变率在肠化、不典型增生、胃癌分别为３７．５％ （３／８），４２．１％（８／１９），５３．３％（１６／３０）。正常组织、浅表胃炎未发现ｐ５３突变。肠化、不典型增生、胃癌与正常对照组、浅表胃炎组相比均存在显著差异（Ｐ＜０．０５，Ｐ＜０．０１，Ｐ＜０．０１）。在肠化、不典型增生病变中未发现Ｅｘｏｎ８的突变，而在胃癌组Ｅｘｏｎ８的突变为４例（４／３０），提示Ｅｘｏｎ８的突变主要发生在晚期。在各病变组未发现Ｅｘｏｎ４、Ｉｎｔｒｏｎ６的突变。对Ｅｘｏｎ４、Ｉｎｔｒｏｎ６、ＡＰＣ基因的杂合缺失研究表明，２５对胃癌标本中有１９对Ｅｘｏｎ４杂合子，杂合率为７６．０％，９对有杂合缺失，ＬＯＨ为４７．４％，２３对Ｉｎｔｒｏｎ６杂合子，杂合率为９２．０％，其中２对为杂合缺失，ＬＯＨ为８．７％，１８对ＡＰＣ杂合子（１８／２５     

胃癌病变术前超声内镜检查分期与p53基因突变的关系

胃癌是常见的消化道恶性肿瘤，术前进行正确的病变分期、判断癌浸润和转移的生物学行为，不仅有助于预后判断，同时也有助于更好的制定治疗计划，因此术前癌肿分期已成为现代医学重要的诊断模式，针对胃癌术前病理取材和分期的研究在临床上具有重大的实际应用价值．业已表明，超声内镜检查（ｅｎｄｏｓｃｏｐｉｃｕｌｔｒａｓｏｎｏｇｒａｐｈｙ，ＥＵＳ）对胃癌术前分期明显优于其他各种检查，与术后病理对照也具有较高的一致性［１］．然而，这种术前分期能否反映胃癌的细胞生物学行为，其术前ＥＵＳ分期的基因改变背景尚未见有研究报告．…     

胃癌p53基因表达与转移及预后的研究

目的观察胃癌组织ｐ５３基因的超表达及其与预后的关系。方法用抗人Ｐ５３基因蛋白单克隆抗体Ｓ＿Ｐ免疫组织化学方法，观察１２８例胃癌组织ｐ５３表达状况，并对ｐ５３表达与胃癌淋巴结转移状态和术后５年生存率进行比较分析。结果胃癌组织１２８例的ｐ５３表达阳性率为４３８％（５６／１２８）；ｐ５３表达阳性和阴性组的胃癌局部和远处淋巴结转移率分别为６７９％（３８／５６）和５１４％（３７／７２），两者经统计学处理无显著性差异（Ｐ＞００５）。获得随访９８例，胃癌术后５年生存率的随访结果显示，ｐ５３阳性和阴性组分别为３８１％（１６／４２）和３０１％（１７／５６），两组间无统计学意义（Ｐ＞００５）。结论胃癌的发生与ｐ５３基因突变关系密切，并可用免疫组化检测，但Ｐ５３基因蛋白在胃癌组织中的超表达，似不能作为判断胃癌预后的参考指标，应进一步探讨     

人肝细胞癌p53异常的预后意义

目的分析和探讨p53异常对人肝细胞癌(HCC)术后复发与生存的影响,以及其在HCC发生发展中的作用机制.方法手术切除HCC标本202例.分别来自启东HCC高发区和上海等一般地区,其中行二次或多次手术患者54例,组织学检测HBsAg阳性患者138例(68.3%),HBV DNA原位杂交检测阳性患者86例(42.6%),采用PCR-SSCP和RFCP技术结合免疫组化示综显示,分析p53基因5,6,7,8外显子突变及其编码蛋白的过度表达.结果 p53基因突变率为44.6%(33/74),其中89.8%(27/73)表现为点突变,18.2%(6/33)为片段性碱基缺失,长度10bp～16bp.等位基因杂合性缺失(LOH)主要集中于外显子7和8,各与39.4%(13/33)和27.3%(9/33).外显子5和6的突变发生率各为18.2%(6/33)和15.1%(5/33).外显子7RFLP分析证实第249位密码子有颠换突变(53.8%,7/13)外,248位密码子也有点突变发生(30.8%,4/13).免疫组化检测显示P53蛋白过度表达的总检出率为70.3%(142/202),pAb1801与CM-1 mAb检测P53蛋白过度表达率分别为69.5%(89/128)和67.2%(86/128),而采用DO-7和pAb240单抗检测的阳性率仅为39.8%(51/128)和19.5%(25/128).蛋白检测的地区差异明显.启东高发区肝癌的P53蛋白过度表达率为81.2%(92/114),而上海等一般地区肿瘤组织的阳性表达率为56.8%(50/88).p53基因突变检测与上述结果雷同,分别为57.1%(16/28)和37.1%(17/46),二者差异显著(P＜0.05).并显示与HBV感染,肿瘤去分化和侵袭行为,以及术后复发及生存时间有关联.结论国人HCC p53基因突变多为非定点错义突变,外显子7上249位密码子仅为HCC常见位点之一,反映除AFB1诱变作用外,还可能有其他环境诱变因素的参与,尤其是HBV感染.由于基因-蛋白质表达上既存在一致性,也可出现不一致性,表明P53蛋白的构型变异不仅来自其编码基因的转录失常,蛋白质自身的变化更是其正常的功能失活的重要机制.地理差异反映病因与致癌机制的复杂性.采用CM-1和pAb1801株mAb检测P53蛋白的过度表达比用PCR-SSCP分析p53基因变化更能反映人HCC的术后复发与预后.     

p53与食管癌研究进展

食管癌是消化系统最具侵袭性的恶性肿瘤之一,发病率和死亡率高,预后差。研究表明,p53基因的突变与食管癌的发生密切相关,p53的表达可作为判断食管癌预后和选择综合治疗方案的参考指标。如何正确分析和评价p53的表达在食管癌中的作用及意义对阐明食管癌的发病机制意义重大。本文总结了p53基因与食管癌的诊断、发生发展、治疗以及预后之间的关系,为后期临床治疗提供可靠依据。     

Correlation of p53 gene mutation and expression of P53 protein in cholangiocarcinoma

AIM: To characterize the tumor suppressor gene p53 mutations and study the correlation of p53 gene mutation and the expression of P53 protein in cholangiocarcinoma. METHODS: A total of 36 unselected, frozen samples of cholangiocarcinoma were collected. p53 gene status(exon 5-8) and P53 protein were examined by automated sequencing and immunohistochemical staining, combined with the clinical parameters of patients. RESULTS: p53 gene mutations were found in 22 of 36 (61.1%) patients. Nineteen of 36 (52.8%) patients were positive for P53 protein expression. There were significant differences in extent of differentiation and invasion between the positive and negative expression of P53 protein. However, there were no significant differences in pathologic parameters between the mutations and non-mutations. CONCLUSION: The alterations of the p53 gene evaluated by DNA sequence analysis is relatively accurate. Expression of P53 protein could not act as an independent index to estimate the prognosis of cholangiocarcinoma.     

肝细胞癌p53基因249密码子热点突变的研究

目的 研究肝细胞癌(HCC)中p53基因249密码子(p53 E7 cd249)点突变情况。方法 用PCR法及HAEⅢ限制性片段长度多态性分析(HAEⅢ/RFLP)检测河南豫东地区38例HCC石蜡包埋组织及2例肝细胞癌株中p53 E7cd249点突变情况,DNA测序证实。选取广西桂西南地区的10例HCC作对照。结果 来自河南豫东地区的HCC p53 E7 cd249点突变率为10.5％(4/38),对照组广西桂西南地区的HCC p53 E7 cd249点突变为40％(4/10),二者相比具有显著性差异(P<0.05)。2例肝细胞癌株中均未发现HCC p53 E7 cd249点突变。结论 河南豫东地区HCC中p53基因E7 cd249点突变为非高发事件;p53 E7 cd249点突变可能发生在肝细胞癌变的晚期。     

p53 allele deletion and protein accumulation occurs in the absence of p53 gene mutation in T-prolymphocytic leukaemia and Sezary syndrome

In a series of 24 patients with chronic T-lymphoid disorders [13 T-prolymphocytic leukaemia (T-PLL) and 11 Sezary syndrome] we have studied (i) chromosome 17p abnormalities and p53 allele deletion by fluorescence in situ hybridization; (ii) mutation in the exons of the p53 gene by direct DNA sequencing; and (iii) p53 protein expression by immunocytochemistry and, in some cases, also by flow cytometry with DO-1, a monoclonal antibody to the p53 protein. The study revealed p53 deletion and accumulation of p53 protein in the absence of mutation in the exons that included the hot-spots and differs from that described in B-prolymphocytic leukaemia. Seven T-PLL and five Sezary syndrome patients had p53 overexpression, and five T-PLL and nine Sezary syndrome patients showed p53 deletion. Although the majority of cases with p53 accumulation had p53 deletion, the proportion of cells with the deletion did not correlate with the proportion of cells positive for p53 expression. Two cases of T-PLL showed strong p53 expression in the absence of p53 deletion, and one case of Sezary syndrome with p53 deletion in 97% of cells did not express p53. These findings suggest that a non-mutational mechanism exists for the accumulation of p53 protein in these T-cell disorders. The oncogenic effect of the accumulating wild-type protein has been reported in other malignancies. Whether haploidy resulting from p53 deletion contributes to this mechanism has yet to be determined. Alternatively, the frequent loss of the p53 gene could be associated with the deletion of an adjacent gene, which could be involved in the pathogenesis of these diseases.     

The mutation of codon 249 in the p53 gene is not specific in Japanese hepatocellular carcinoma

ABSTRACT— Hepatocellular carcinoma samples obtained from 59 patients at surgical resection were examined for mutations of the third base at codon 249 of the p53 gene, using the polymerase chain reaction and oligonucleotide hybridization techniques. This point mutation, which is frequently observed in HCC cases from Southern Africa and Quidong in China, was not recognized in either 60 hepatocellular carcinomas or 53 noncancerous liver tissue samples from Japan. Thirty-four of 45 patients (75.6%) were positive for the hepatitis C virus, which was a higher rate than that for hepatitis B virus infection (9 of 55; 16.4%). The exposure to aflatoxin B1 was not considered to be remarkable. These results suggest that the point mutation of the third base at codon 249 is not common in Japanese patients, and it is suggested that numerous other factors affect the mutation of the p53 gene and the development of hepatocellular carcinoma.     

Colorectal carcinoma prognosis can be predicted by alterations in gene <Emphasis Type="Italic">p53</Emphasis> exons 5 and 8

Background and aims Gene p53 alteration is a genetic event described in the progression from adenoma to colorectal carcinoma. Most of the p53 mutations occur in exons 5 to 8 in highly preserved regions and in the three main structural domains of the p53 protein. It is possible that mutations affecting different structural regions may present different effects on the p53 protein function and, due to this, they may have different prognostic meaning. Materials and methods The study population consisted of 353 patients diagnosed with sporadic colorectal cancer. Mutations in 5–8 exons of p53 gene were detected by means of single strand conformation polymorphism (SSCP). All samples that showed different migration bands in SSCP were confirmed by sequencing. Results A total of 69 patients (19.7%) showed alterations of the gene p53. It was observed that mutation in codon 175 in exon 5 was related to tumors located in the colon (p = 0.01) and the mutation in the codon 288 in exon 8 was related to rectal tumors (p = 0.02). In the study of overall survival, mutation in codon 175 of exon 5 conferred a better prognosis and alterations of exon 8 were related to a worse prognosis in different population subgroups: in men, in patients younger than 71 years old, in the tumors located in the proximal colon, the ones moderately differentiated, and those that are mucinous. Conclusion According to this study, mutations in different exons of p53 are related to different phenotypes in colorectal cancer. These phenotypes could mean differences in the clinical evolution of the patients. This study was supported by grant no. PI030514 from the Fondo de Investigaciones Sanitarias, Spain.     

肝细胞癌mdm2基因表达及其与p53基因突变的关系

目的研究ｍｄｍ２基因在原发性肝细胞癌（ＨＣＣ）中的表达并探讨其与ｐ５３基因突变的关系．方法用银染ＰＣＲＳＳＣＰ法检测ｐ５３基因第５～８外显子的突变,原位杂交检测ｍｄｍ２基因ｍＲＮＡ的表达,ＳＡＢＣ法检测ｍｄｍ２蛋白的表达．结果３９３％（１１／２８）的病例有异常的电泳迁移率．ｐ５３基因突变与肿瘤的大小、分化及转移无关．原位杂交显示９例ＨＣＣ出现ｍｄｍ２基因ｍＲＮＡ增加,７例ＨＣＣ可检测到ｍｄｍ２蛋白表达,ｍｄｍ２基因表达与ＨＣＣ的大小、分化及是否转移无关．Ⅰ～Ⅱ级ＨＣＣ中ｍｄｍ２阳性表达率（１３３％）明显低于Ⅲ～Ⅳ级ＨＣＣ中的阳性表达率（５３８％）．１１例有ｐ５３基因突变的ＨＣＣ中,只有３例出现ｍｄｍ２基因表达,另外６例有ｍｄｍ２过表达的ＨＣＣ未见ｐ５３基因突变．ｐ５３基因突变的ＨＣＣ与ｐ５３基因无突变的ＨＣＣ相比,ｍｄｍ２基因表达阳性率无显著差别．结论ｐ５３基因突变和ｍｄｍ２基因表达在原发性ＨＣＣ的发病中起重要作用．ｍｄｍ２基因表达与ＨＣＣ的恶性程度相关．ｍｄｍ２基因表达与ｐ５３基因是否突变无关．     

结直肠癌部位与p53基因突变的关系

目的：进一步阐明ｐ５３外显子突变率与结、直肠癌不同部位之间的关系。方法：选取１０８例大肠癌患者癌灶组织，用ＰＣＲ－ＳＳＣＰ法进行Ｐ５３第５～８外显子的检测。结果：１０８例大肠癌标本中，５３例发生Ｐ５３基因突变，突变率为４９．０７％（５３／１０８），统计学处理结果表明，外显子与大肠癌部位有显著关系（Ｘ~２＝７３．６８３，Ｐ＜０．００１）。结论：不同部位的大肠癌患者其ｐ５３基因第５～８外显子的突变率不同，筛选最有效的外显子进行检测，可有效地提高检测效率，降低检测成本，减轻病员负担，并在临床推广应用中起积极作用。