Specific intronic p53 mutation in esophageal squamous cell carcinoma in Southern Thailand

AIM:To investigate p53 mutations in esophageal cancer in a high-risk population,and correlate them with smoking,alcohol consumption and betel chewing.METHODS:One hundred and sixty-five tumor samples of esophageal squamous cell carcinoma(ESCC) obtained from a university hospital in Songkhla province,Southern Thailand were investigated for p53 mutations in exons 5-8,using polymerase chain reaction-single strand conformation polymorphism analysis,followed by direct sequencing.A polymerase chain reactionrestric...     

p53 protein in esophageal mucosa of individuals at high risk of squamous cell carcinoma of the esophagus

Squamous cell carcinoma of the esophagus (SCCE) is diagnosed late and carries a poor prognosis. Biomarkers such as p53 protein expression may be present in the esophageal mucosa long before esophageal symptoms or lesions appear and may point toward early diagnosis. Asymptomatic subjects at high risk for SCEE (consumption of more than 80 g of ethanol and 10 cigarettes/day for at least 10 years) underwent upper gastrointestinal endoscopy with biopsies of the esophageal mucosa, and expression of p53 protein was compared with conventional histologic findings. In 182 subjects studied, p53 protein was expressed in a stepwise fashion according to the severity of the histologic findings: normal mucosa (12/103 or 11.7%), mild chronic esophagitis (6/43 or 14%), moderate chronic esophagitis (4/18 or 22.2%), severe chronic esophagitis (1/3 or 33.3%), low-grade dysplasia (4/11 or 36.4%), high-grade dysplasia (2/2 or 100%), and squamous cell carcinoma (2/2 or 100%) (P=0.00025). The odds ratio and confidence intervals were calculated by logistic regression, with multivariate adjustment for potentially confounding variables. The risk for p53 expression was twofold for moderate and severe chronic esophagitis and 10-fold for dysplasia and cancer (P=0.001). p53 protein was expressed not only in cancerous lesions, high-grade and low-grade dysplasia, as expected, but also in mucosa considered normal or with chronic esophagitis using conventional histology. Smokers and alcohol drinkers with normal mucosa or chronic esophagitis that express p53 protein may represent an unrecognized subgroup of individuals that may benefit from surveillance. Follow-up studies of these asymptomatic subjects and molecular analysis of the p53 gene are needed to clarify this point.     

人乳头状瘤病毒HPV-E6及P53蛋白与食管鳞癌关系

目的研究人乳头状瘤病毒HPV-E6和p53在食管鳞癌中的表达,以探讨它们在食管鳞癌中发生发展的生物学意义.方法应用LSAB免疫组化方法对16例正常食管粘膜,18例慢性炎症,22例不典型增生以及60例食管鳞癌组织进行HPV-E6和P53蛋白表达的研究.结果在正常食管粘膜、慢性炎症、不典型增生及食管鳞癌中HPV-E6蛋白阳性率分别为37%,39%,50%及73%,P53蛋白阳性率在上述四组中则为0%,6%,41%及63%.四组比较,HPV-E6和P53蛋白表达均有显著差别(P＜0.05).在60例食管鳞癌Ⅰ,Ⅱ,Ⅲ级分组中,HPV-E6阳性率分别为59%,78%和85%,p53阳性率则分别为45%,67%,80%.三个分级组比较,HPV-E6和P53蛋白表达均有显著差别(P＜0.05). 结论HPV-E6及p53与食管鳞癌的发生发展有着一定相关性,且HPV-E6及p53共同作用很可能更为食管鳞癌发生发展的重要因素.     

Correlation of p53, MDM2 and p14ARF protein expression in human esophageal squamous cell carcinoma

Purpose  

To determine the interrelationships of p53, MDM2, and p14^ARF protein expression in primary esophageal squamous cell carcinoma (ESCC) and their prognostic value in ESCC.     

p53蛋白在口腔鳞癌中的表达

目的 通过对突变型p53蛋白在口腔鳞癌组织中表达的观察,分析p53与口腔鳞癌临床病理特征之间的关系,探讨p53在口腔鳞癌发生中的作用机制。方法 利用免疫组化(P-V法)检测116例患者口腔鳞癌组织及10例正常人口腔黏膜组织中突变型p53蛋白的表达情况。结果 p53蛋白在正常人口腔黏膜和口腔鳞癌组织中的表达率分别为20％、63.8％,二者比较差异有统计学意义(X2=5.660 4,P<0.05);口腔鳞癌在不同病理分级时,p53蛋白表达差异有统计学意义(X2=7.536 2,P<0.05);p53蛋白表达与年龄、性别、发生部位及有无淋巴结转移无相关性。结论 突变型p53蛋白表达与口腔鳞癌的发生有关。不同病理分级,p53蛋白表达也不同。     

The expression of p53, p16, cyclin D1 in esophageal squamous cell carcinoma and esophageal dysplasia]

BACKGROUNDS/AIMS: p53 is known to play a central role in sensing and signaling for the growth arrest and apoptosis in cells with DNA damage. Mutation of p53 is a frequent event in esophageal squamous cell carcinoma (ESCC). p16 protein binds to cyclin dependent kinase 4 (CDK4) inhibiting the ability of CDK4 to interact with cyclin D1, and stimulates the passage through the G1 phase of cell cycle. We observed the expression patterns and frequencies of p53, p16, and cyclin D1 in esophageal dysplasia and in esophageal squamous cell carcinomas. METHODS: In 15 patients of ESCC, 5 patients of esophageal dysplasia and 5 volunteers with normal esophagus, tissue specimens were taken from esophageal lesions during the operation or endoscopic examination. We used specific monoclonal antibodies for p53 protein, p16(INK4 ) protein and cyclin D1. Immunoreactivity was scored. RESULTS: Mean age of all groups was 66 years old (range 47-93) and men to women ratio was 19:1. p53 mutation was observed in 87% (13/15) of ESCC, in 80% (4/5) of esophageal dysplasia, in 0% (0/5) of normal mucosa (p=0.001). p16 expression was seen in 40% (2/5) of esophageal dysplasia, 27% (4/15) of ESCC and 100% (5/5) of normal mucosa (p=0.016). Cyclin D1 expression was not significantly different among 20% (1/5) of esophageal dysplasia, 53% (8/15) of ESCC and 20% (1/5) of normal mucosa. Either the expression of p53 mutation or the loss of p16 occurred in 80% (4/5) of esophageal dysplasia and in 93% (14/15) of ESCC. CONCLUSIONS: The expression of p53 mutation and the loss of p16 might play a central role in the pathogenesis of esophageal squamous cell carcinoma (ESCC), and contribute to the development of precancerous lesion such as dysplasia. In addition, there is a possibility that the mutations of p53 and p16 silencing would be the early events in ESCC development.     

Five-year postsurgical monitoring of serum p53 antibody for locally advanced esophageal squamous cell carcinoma

Serum p53 antibody (s-p53-Ab) titers were postoperatively monitored for over 5 years in a 67-year-old man with locally advanced esophageal squamous cell carcinoma. The tumor stage was classified as clinical stage II (cT3N0M0). Serum SCC antigen (s-SCC-Ag; 6.2 ng/mL) and s-p53-Ab (3.83 U/mL) were noted to be positive before surgery. Radical esophagectomy with three-field lymph node dissection was performed without neoadjuvant therapy. Pathological findings of the surgically resected specimens revealed a stage II tumor (pT3N0M0). Postoperatively, the patients did not receive any adjuvant therapy. Although the s-SCC-Ag was found to be negative at 2 months postoperatively, s-SCC-Ag was found to be six times positive despite no signs of recurrence. The s-p53-Ab titers constantly decreased to less than the cutoff value at 6 months postoperatively and continuously decreased over 5 years postoperatively. Finally, s-p53-Ab titers became less than the detection limit value at 60 months postoperatively. No recurrence was observed throughout the postoperative course. This case report is the first to describe the five-year monitoring of postoperative changes in s-p53-Ab titers in a patient with locally advanced esophageal squamous cell carcinoma without recurrence. s-p53-Ab titers seemed to be more useful than s-SCC-Ag for disease monitoring in this case.     

Prognostic significance of high serum p53 antibody titers in patients with esophageal squamous cell carcinoma

Background

The p53 protein overexpression that usually results from genetic alterations reportedly induces serum antibodies against p53. However, little information is available about the prognostic significance of perioperative serum p53 antibody (s-p53-Abs) titers in patients with esophageal squamous cell carcinoma.

Methods

In this study, we retrospectively evaluated the clinical significance of perioperative s-p53-Abs in 135 patients with esophageal squamous cell carcinoma. Of these, 58 patients received neoadjuvant chemotherapy comprising 5-FU and CDDP. While the cutoff level at 1.3 U/ml indicated seropositive patients, level of 13.4 U/ml was used to identify high-titer patients. We monitored serum titers seropositive patients after surgery and evaluated the prognostic significance by the univariate and multivariate analyses.

Results

In this study, 29 patients (21.5%) were positive for s-p53-Abs before treatment. The frequency of both seropositive patients and high-titer patients (>?13.4 U/ml) was not significantly associated with tumor progression. While seropositive patients did not demonstrate significant poor overall survival, high-titer patients demonstrated significant poor overall survival based on the multivariate analysis (P?<?0.001). Moreover, the s-p53-Abs titer did not correlate with the response to neoadjuvant chemotherapy. Among seropositive patients, the negative conversion of s-p53-Abs more likely led to be long-term survival.

Conclusions

This study determined that the high-titer of s-p53-Abs was an independent risk factor to reduce the overall survival of patients with esophageal cancer patients. The negative conversion of s-p53-Abs could be a good indicator of favorable prognosis.

     

Association of p53/p21 expression with cigarette smoking and prognosis in esophageal squamous cell carcinoma patients

factors,such as cigarette smoking,in esophageal squamous cell carcinoma(ESCC)in northeastern Iran,a region with a high incidence of ESCC.METHODS:The expression of p53 and p21 proteins was investigated immunohistochemically in tumor tissue from 80 ESCC patients and in 60 available paraffinembedded blocks of adjacent normal specimens from the cases,along with normal esophageal tissue from 80 healthy subjects.RESULTS:Positive expression of p53 protein was detected in 56.2%(45/80)of ESCC cases,and in none of the normal esophageal tissue of the control group(P<0.001).Furthermore,73.8%(59/80)of ESCC cases and 43.8%(35/80)of controls had positive expression of p21 protein(P<0.001).Cigarette smoking was significantly associated with p53 over-expression in ESCC cases(P=0.010,OR=3.64;95%CI:1.32-10.02).p21 over-expression was associated with poorer clinical outcome among the ESCC patients(P=0.009).CONCLUSION:Over-expression of p53 in association with cigarette smoking may play a critical role in ESCC carcinogenesis among this high-risk population of northeastern Iran.Furthermore,p21 over-expression was found to be associated with poor prognosis,specifically in the operable ESCC patients.     

Changes of serum p53 antibodies and clinical significance of radiotherapy for esophageal squamous cell carcinoma

AIM： To explore the relationship between serum p53 antibodies （p53-Abs） and clinicopathological characteristics and therapeutic effect in patients with esophageal carcinoma （EC）, and to investigate sequential changing regularity of serum pS3-Abs after radiotherapy.
METHODS： The serum pS3-Ab levels were detected in 46 EC patients and 30 healthy adults by enzyme linked immunosorbent assay （ELISA）. The blood samples were collected on the day before radiotherapy and on the administration of an irradiation dose of 20 Gy/10 f/12 d, 40 Gy/20 f/24 d and 60 Gy/30 f/36 d after radiotherapy.
RESULTS： The level and positive rate of serum pS3-Abs in EC patients were significantly higher than those in normal individuals （P 〈 0.05）. Serum anti-p53 antibodies were positive in 18 of 46 EC patients （39.1%）. The positive rate of pS3-Abs in EC was related to histological grade, disease stage and lymph node metastasis （P 〈 0.05）, but it was not significantly related to sex, age and to the size and site of tumor. The level and positive rate of p53-Abs had significant differences between before radiotherapy and after administration of an irradiation dose of 40 Gy/20 f/24 d and 60 Gy/30 f/36 d （P 〈 0.05 orP 〈 0.01）. The positive rate of p53-Abs in EC patients with effect was significantly lower than that in those without effect after radiotherapy （P 〈 0.0001）.
CONCLUSION： Detection of serum p53-Abs is helpful to the diagnosis of esophageal carcinoma. Monitoring for sequential change of serum p53-Abs before and after radiotherapy in patients with esophageal carcinoma is also useful to evaluate the response to the treatment and prognosis of the patients.     

Serum p53 antibody as a predictor of early recurrence in patients with postoperative esophageal squamous cell carcinoma

It is reported that surveillance of serum p53 antibody (Ab) is a useful marker in detecting esophageal squamous cell carcinoma (ESCC). But there is little reported about prognostic significance of serum p53-Ab in postoperative patients with ESCC. The aim of this study is to evaluate the significance of preoperative serum p53-Ab as a marker of early recurrence after curative resection for ESCC. Enzyme-linked immunosorvent assay (ELISA) was used to analyze serum p53-Ab before treatment in 44 patients with ESCC. Carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC-Ag) were examined by immunoradiometric assay. The patients who were strongly positive and positive in serum p53-Ab were more likely to have early recurrence after curative resection than seronegative patients. There were no significant correlations between CEA, SCC-Ag positivity and early recurrence. We found that serum p53-Ab was useful to predict a risk of early recurrence after curative surgical resection for ESCC.     

The clinicopathological significance of p21 and p53 expression in esophageal squamous cell carcinoma: an analysis of 153 patients

OBJECTIVE: The p21 gene is thought to play a central role in tumor suppression. The aim of this study was to examine the clinicopathological role of p21 and p53 in esophageal squamous cell carcinomas. METHODS: The expression of p21 and p53 proteins in 153 Chinese patients (131 men, 22 women) with resected esophageal squamous cell carcinomas was investigated by the immunohistochemical method. Correlation between p21 and p53 expression and clinicopathological features was examined. RESULTS: The expression of p21 and p53 was detected in 70% and 64% of the tumors, respectively. The staining of p21 and p53 was also found in squamous carcinoma in situ, dysplasia, and nontumor epithelium. p21 expression was often weak in the suprabasal cells and found in better differentiated tumors. There was no significant correlation between the expression of p21 and the abnormal accumulation of p53. The prognosis of the patients depended on the size, stage, and p21 expression of the lesion. In stage III lesions with tumor diameter < or = 7.5 cm (n = 93), patients with loss of p21 expression had better survival. The survival rates of patients were worse if they had expression of both p21 and p53. CONCLUSIONS: Thus, p21 and p53 had prognostic value for esophageal squamous cell carcinomas. Loss of p21 expression was shown without p53 alternations, indicating that other mechanisms are also involved in turning off the gene. The pattern of p21 and p53 expression predicts an aggressive clinical course of esophageal squamous cell carcinomas.     

Overexpression of Ets-like protein 1 in human esophageal squamous cell carcinoma

INTRODUCTION Esophageal cancer ranks among the 10 most frequent cancers in the world, with a predominant distribution in developing countries. It is one of the most common malignant tumors in China[1,2]. Our previous study showed that genetic susceptibili…     

DAPK mRNA和蛋白在食管鳞癌组织中的表达及意义

目的:探讨河南省食管癌高发区居民食管鳞癌组织中DAPK mRNA和蛋白的表达特征及意义.方法:应用原位杂交和免疫组织化学法检测50例食管鳞癌组织、17例癌旁不典型增生组织及20例正常食管黏膜组织中DAPK mRNA和蛋白的表达,并分析DAPK表达与临床病理特征的关系.结果:在食管鳞癌癌变过程中DAPK在正常黏膜组织、癌旁不典型增生组织及癌组织中mRNA及蛋白的表达组间比较有明显差异(X2 =14.655,7.998,均P<0.05);不同TNM分级及有无淋巴结转移的食管鳞癌组织之间DAPKmRNA及蛋白表达差异均有统计学意义(均P<0.05).DAPK mRNA及蛋白食管鳞癌组织中的表达呈正相关关系(γ=0.743,P=0.000).结论:食管鳞癌组织中DAPK mRNA与蛋白表达均降低,其表达降低或者缺失可能与食管鳞癌发生发展有关;检测DAPK mRNA及蛋白的表达有望成为食管鳞癌早期诊断和判断预后的分子指标之一.     

Expression of apoptosis-regulating proteins p53, Bcl-2, and Bax in primary resected esophageal squamous cell carcinoma

Apoptosis plays a key role in the pathogenesis, aggressiveness, and therapy responsiveness of cancer. Proteins of the Bcl-2 family as well as p53 are important regulators of apoptosis. The present study retrospectively examines the expression of apoptosis-regulating proteins in primary resected esophageal squamous cell carcinoma (ESCC) and the correlation between the outcome of patients' treatment and the expression of the proteins. We used antibodies specific for the human p53, Bcl-2 and Bax proteins to examine the expression of these apoptosis-regulating proteins in 40 archival specimens of patients with primary resected esophageal squamous cell carcinoma. The overall expression of p53, Bcl-2, and Bax was 73%, 18%, and 100%, respectively. No significant correlations were found between the expression of p53, Bcl-2, and Bax. The expression of Bcl-2 had a negative influence on survival in this population of primary resected ESCC patients (p=0.03). But no differences in survival were observed in relation to the expression of p53 or Bax. In conclusion, Bcl-2 expression may provide additional and prognostic information for the clinical course of the disease and therefore to be developed as a prognostic indicator for primary resected esophageal squamous cell carcinoma.     

Immunohistochemistry assessment of p53 protein in Basal cell carcinoma

The most frequently mutated tumor suppressor gene found in human cancer is p53. In a normal situation, p53 is activated upon the induction of DNA damage to either arrest the cell cycle or else induce apoptosis. However, when mutated, p53 is no longer able to properly accomplish these functions. Our aim was to investigate p53 protein alteration in cases of basal cell carcinoma (BCC) and compare it with the control group. We investigated P53 gene expression in 41 cases of basal cell carcinoma and 20 patients with benign skin disease as control group. The alteration of p53 protein was investigated by immunohistochemistry method. The Data were analyzed using SPSS package, T and Chi-Square tests.Twenty eight out of 41 basal cell carcinoma and 3 out of 20 control were p53-mutated, and there was a statistically significant difference in cases of BCC in comparison with controls (x2 test; p= 0.0001).Taken together, showing alteration of p53 protein, our findings could add to the knowledge that might contribute to the self-maintenance of cancer cells and development of basal cell carcinoma.     

Coexpression of vascular endothelial growth factor and p53 protein in squamous cell carcinoma of the esophagus

OBJECTIVE: p53 plays a role in tumor angiogenesis, and vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. The aim of the present study was to clarify how expression of p53 protein participates in angiogenesis, and whether the coexpression of VEGF and p53 protein has a significance for angiogenesis and the clinicopathological features in esophageal squamous cell carcinoma (SCC). METHODS: Tissues samples were taken from 60 patients with esophageal SCC after surgery. The expression of VEGF and p53 protein in these SCC was examined immunohistochemically. Microvessel density (MVD) was determined by counting microvessels in tumor sections stained for Factor VIII-related antigen. Ki-67 labeling index (LI) was calculated, based on Ki-67 antigen immunostaining, as a proliferative marker. Apoptotic index (AI) was calculated, based on the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling, to evaluate apoptosis. RESULTS: VEGF expression was observed in 58.3%, and p53 protein expression was observed in 61.7% of the 60 patients. VEGF and p53 protein were significantly coexpressed in 26 (43.4%). Histological venous invasion (p < 0.01) and distant metastasis (p < 0.05) were significantly correlated with p53 protein expression. The two parameters were more frequently observed in the SCC with VEGF/p53 coexpression than in those without the coexpression. The MVD and Ki-67 LI were significantly higher (p < 0.01 and p < 0.001), and the AI was significantly lower (p < 0.001) in the SCC with p53 protein expression than in the SCC without it. The MVD and Ki-67 LI were higher, and the AI was lower in the SCC with VEGF/p53 coexpression than in those without the coexpression. The 5-yr survival rate in patients with the coexpression was poorer than in the other patients. CONCLUSION: These results suggest that mutant p53 expression is associated with angiogenesis and distant metastasis in esophageal SCC, and that the coexpression of p53 and VEGF may play an important role in angiogenesis, and have important clinical significance.     

食管黏膜凋亡增殖和p53表达的增龄变化与食管鳞癌的关系

目的探讨食管黏膜增殖凋亡和p53表达的增龄变化以及这些变化与食管鳞癌的关系。方法按年龄分层选择连续胃镜检查对象818例,男414例,女404例。分为青中年组（258例）、老年前期组（296例）和老年组（264例）,进行食管活组织检查,应用TUNEL法检测凋亡指数（AI）,免疫组化法检测增殖指数（PI）和p53表达。结果食管正常上皮→单纯增生→轻中重度异型增生→鳞癌的发展过程中,AI等级逐渐下降,PI等级和p53表达逐渐增高。在食管正常上皮中,AI等级青中年组〉老年前期组〉老年组;PI等级比较,老年前期组分别高于青中年组和老年组（P〈0.01）;p53表达在老年前期组和老年组均高于青中年组（P〈0.01）。非条件logistic回归分析,食管鳞癌独立危险因素为增龄、PI等级和p53表达。当食管黏膜PI等级明显增高伴p53阳性时,鳞癌检出率明显增高,轻中重度异型增生有增高趋势,老年人尤为突出。结论食管黏膜正常上皮随增龄出现增殖凋亡和p53表达变化,与食管黏膜癌变过程变化相似,老年人食管黏膜PI明显增高伴p53阳性可作为食管鳞癌和癌前病变进一步随访和筛查的线索。