p21/waf1/cip1 in gastric cancer: associations with histopathological subtypes, lymphonodal metastasis, prognosis and p53 status

BACKGROUND: Cyclins and cyclin-dependent kinases are determining factors of the cell cycle. In the present study, we investigated the role of p21 and p53 in the biology of gastric cancer, focusing on its influence on progression and prognosis (n = 195). METHODS: P21 and p53 immunoreactivity was analysed immunohistochemically, applying monoclonal antibodies. The p53 status was comparatively evaluated by PCR-SSCP analysis of p53 mutations in selected tumours. RESULTS: Fifty-eight percent of the carcinomas were p21+ in more than 5% of the cancer cell nuclei, whereas 19% exhibited a p21 immunoreactivity in more than 20% of the nuclei. On the other hand, p53 was over-expressed (in more than 50% of the nuclei) in about 45% of the specimens. P21 immunoreactivity in more than 5% of the nuclei was inversely related to the pN as well as pTNM cancer stage, whereas only a strong p21 expression (in >20% of the nuclei) was correlated with a better survival probability in a univariate analysis. The p53 status was associated with lymphonodal metastasis, but not with prognostic data. In multivariate survival analyses, neither p21 nor p53 emerged as independent prognostic factors. Compared with the results of p53 mutation analysis by PCR-SSCP. p21 immunoreactivity was reduced in p53-mutated cases. CONCLUSIONS: These features show an association of p21 over-expression with certain clinico-pathological parameters of gastric cancer. In this context, our data suggest that p21 immunoreactivity in more than 5% of the tumour cells has a predictive value for the course of adenocarcinoma of the stomach.     

Expression of p53 and p21WAF1/CIP1 Proteins in Gastric and Esophageal Cancers (Comparison with Mutations of the p53 Gene)

The p53 gene has been shown to be commonlymutated in various human cancers, and mutant p53 can actas a dominant oncogene. The intact p53 protein is alsoknown to induce the cyclin-dependent kinase inhibitor p21^WAF1/CIP1 and is implicated incell cycle arrest. We investigated p53 gene alterationsin gastric adenocarcinoma and esophageal squamous cellcarcinoma to elucidate the association of the nuclearaccumulation of the p53 protein and/orp21^WAF1/CIP1 protein. Abnormalities of thetumor suppressor gene p53 protein and the expression ofp21^WAF1/CIP1 protein were analyzed byimmunohistochemical techniques in 32 cases of gastric adenocarcinoma and 15 cases ofesophageal squamous cell carcinoma. Twenty cases ofgastric cancer and five cases of esophageal cancer werealso analyzed for p53 gene mutation by polymerase chain reaction and direct nucleotide sequencing.Overexpression of p53 protein was found in 13/32 (41%)of gastric cancers and 5/15 (33%) of esophageal cancers.We found immunodetectable p53 in 10/14 cases with mutations and in none of 11 cases withoutmutations in gastric and esophageal cancers. Hence,immunohistochemical and genetic analyses gave concordantresults in 84% of 25 cases, revealing a good correlation between immunostaining of p53 and missensemutation of the p53 gene. p53 immunostaining was notobserved in cases with frameshift or splicing mutation.The expression of p21^WAF1/CIP1 protein wasfound in 9/32 (29%) of gastric cancers and 4/15 (27%) ofesophageal cancers and in 2/14 (14%) cases withalteration of the p53 gene and in 5/11 (45%) without.These results suggest that abnormalities of p53 may be closely associated with the pathogenesisof gastric adenocarcinoma and esophageal squamous cellcarcinoma and that the immunoreactivity of p53 proteinis a general indicator of the tumors with altered p53 function. The expression ofp21^WAF1/CIP1 protein was suppressed in theneoplastic tissues with and without p53 genealteration.     

Expression of p53 and p21 Are Independent Prognostic Factors in Patients with Serosal Invasion by Gastric Carcinoma

To evaluate whether the expression of p53 andthat of p21 are independent prognostic factors inpatients with advanced gastric cancer, we investigatedclinicopathological factors and the expression of p53 and p21 in 158 patients with gastric cancerthat had invaded the serosa and who had undergonecurative gastrectomy. In multivariate survival analysisof 156 surviving patients, we evaluated the size of the tumor, lymph node metastasis, venousinvasion, lymph node dissection, expression of p53, andexpression of p21 as independent prognostic factors.Moreover, we divided patients into four groups according to the expression of p53 and p21 in theirtumors [group A, p53^-/p21^-, N = 40(one died within 30 days of surgery); group B, p53^-/p21^-, N = 23; group C,p53⁺/p21⁺, N = 58; and group D,p53⁺/p21⁺, N = 37 (one died within 30 days of surgery)]. The 5- and 10-yearsurvival rates of 39 patients in group A were 71.7% and64.3%, those of 23 patients in group B were 81.4% and81.4%, those of 58 patients in group C were 35.6% and 30.2%, and those of 36 patients ingroup D were 67.9% and 60.7%. The prognosis of patientsin group C was poorer than that of patients in the otherthree groups. This result indicates that the evaluation of the expression of both p53 andp21 expression might provide prognostic information thatis more accurate than that provided by evaluation of theexpression of p53 alone.     

p53 Expression in Gastric Cancer (Clinicopathological Correlation and Prognostic Significance)

For evaluation of the prognostic relevance ofp53 expression in gastric cancer, theimmunohistochemical tissue status of 133 primary gastriccancer patients was investigated for p53 expression andthe association between p53 tissue status andclinicopathological parameters was analyzed. P53immunoreactivity was detected in the nuclei of cancercells in 35 cases (26.3%). The nuclear p53immunoreaction was closely associated with tumor location, lymph nodemetastasis, and curability. Tumors with positive p53stain reactions frequently metastasized to lymph nodes(metastatic rate: 91.4%) in contrast to tumors with negative p53 stain reactivity (71.4%, P =0.021). Immunohistochemical analysis of primary gastriccancer appears to be an accurate and simple method ofscreening for p53 expression. In combination with common prognostic parameters, determination of p53tissue status might help to detect prognosticallyunfavorable subgroups of gastric cancerpatients.     

Prognostic significance of Bcl-2 and p53 expression in gastric cancer

Background and aims Apoptosis regulates cell death and influences cell proliferation and therefore may play an important role in development or growth of various malignant tumors. The Bcl-2 and p53 are closely linked in the regulation of apoptosis. We investigated the prognostic significance of Bcl-2 and p53 expression in patients with gastric cancer.Patients and methods Immunohistochemistry was used to study Bcl-2 and p53 expression in 308 consecutive patients with gastric cancer.Results Bcl-2 expression was positive in 39 patients (12.7%) and showed a significant negative correlation with depth of invasion and lymph node metastasis. p53 expression was observed in 105 patients (34.1%) and was significantly associated with depth of invasion, lymph node metastasis, distant metastasis, and intestinal type. Patients with Bcl-2⁺ tumors showed a trend to better 5-year survival rate (81%) than those with Bcl-2^– negative tumors (71%). The 5-year survival rate in p53 positive cases (60%) was significantly lower than that in p53-negative cases (78%). In addition, p53 expression showed a significantly poorer prognosis in both diffuse and intestinal types. In multivariate analysis restricted to patients with R0 resection p53 expression was an independent prognostic factor (relative risk: 2.063). In combined assessment of p53 and Bcl-2 expression the group with p53⁺/Bcl-2^– tumors showed significantly worse 5-year survival (57%) than the other groups, while best survival was seen in the group with p53⁺/Bcl-2⁺ tumors (100%).Conclusion p53 expression is an unfavorable prognostic factor in gastric cancer. Bcl-2 expression may have possible prognostic value when combined with p53 expression.     

p53 expression,K-ras gene mutation and microsatellite instability in gastric B-cell lymphomas

BACKGROUND AND AIMS: Genetic mechanisms involved in the development of gastric B-cell lymphomas remain unclear. The aim of the present study was to clarify the roles of mutations of the p53 and K-ras genes, and microsatellite instability (MSI) in the development of gastric B-cell lymphomas. METHODS: We investigated p53 immunoreactivity, mutations of the K-ras gene, and MSI in 27 gastric marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue type (MZBCL) and 24 diffuse large B-cell lymphomas (DLBCL). p53 immunoreactivity was examined using a monoclonal antibody, DO-7. Mutation of the K-ras gene was detected by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. MSI was examined at five microsatellite loci with a microsatellite assay. Cases were classified as having high-frequency MSI (MSI-H) (>/= 2 loci showing instability), low-frequency MSI (MSI-L) (only one locus showing instability), or as microsatellite stable. RESULTS: p53 immunoreactivity was detected in 1 of 16 (6%) MZBCL and 8 of 19 (42%) DLBCL. Frequency of p53 immunoreactivity in DLBCL was significantly higher than that in MZBCL (P = 0.018). MSI-H was detected only in 1 of 20 (5%) DLBCL. None of the cases examined showed mutation of the K-ras gene. CONCLUSIONS: These data suggest that mutations of the p53 gene may play an important role in the development of gastric DLBCL, and that mutations of the K-ras gene and MSI may be involved in little part of the development of gastric B-cell lymphomas.     

The Prognostic Value of UHRF-1 and p53 in Gastric Cancer

Background/Aims:

This study aimed to examine whether UHRF-1 and p53 overexpression is a prognostic marker for gastric cancer.

Patients and Methods:

Sixty-four patients with gastric cancer (study group) and 23 patients with gastritis (control group) were evaluated. Immunohistochemistry was used to examine expression of UHRF-1 and p53 in gastric cancers and a control group diagnosed with gastritis.

Results:

The median age was 63 years (18-83 years) in the study group. UHRF-1 was positive in 15 (23%) patients with gastric cancer and five (21.7%) patients with gastritis (P = 0.559). UHRF1 expression level in gastric cancer is more powerful than in gastritis (P = 0.046). Thirty-seven (61%) patients with gastric cancer and only one patient with gastritis were p53 positive (P < 0.001). After a median follow-up of 12 months (1–110), the 2-year overall survival rates were 55% and 30% in negative and positive p53, respectively (P = 0.084). Also, the 2-year overall survival rates were 45% and 53% in negative and positive UHRF-1, respectively (P = 0.132).

Conclusion:

According to this study, UHRF-1and p53 were not prognostic factors for gastric cancer, whereas they may have a diagnostic value for differantiating between gastric cancer and gastritis.Key Words: Gastric cancer, p53 genes, prognosis, survival, UHRF-1 proteinGastric cancer is one of the most frequent cancers in the world, for both men and women. Gastric cancer is the fourth most frequent cancer and is the second leading cause of cancer-related death worldwide. Nearly two-thirds of stomach cancers occur in developing countries.[1] Despite innovations in treatment modalities, gastric cancer still remains a mortal disease.[2] Gastric cancer is more frequent in the Eastern population and in Turkey than in the European population. It is the second leading cause of cancer death in men, and the third leading cause in women in Turkey.[3] Unfortunately, diagnostic and prognostic markers are insufficient for this mortal and frequent tumor.Epigenetic silencing of tumor suppressor genes is a hallmark in human cancers affecting multiple cellular pathways, such as cell signaling, adhesion and invasion, cell cycle, angiogenesis, DNA repair, and apoptosis.[4,5] Epigenetic alterations contribute significantly to the development and progression of gastric cancer.[6] Ubiquitin-like, containing PHD and RING finger domains 1 (UHRF1) is a newly discovered gene reported to have a function in maintaining DNA methylation by helping recruit DNA methyltransferase 1 (DNMT1) to hemimethylated DNA.[7] UHRF1 is a putative oncogenic factor and, is overexpressed in numerous cancers.[8,9,10,11,12] There is insufficient data on the role of UHRF-1 in gastric carcinoma in the literature.P53 is a well-known tumor suppressor gene and many human cancers are found to have a mutant p53 gene. In gastric carcinomas, p53 expression frequency has been reported to vary from 25% to 60%.[13,14,15,16] Its prognostic role in gastric cancer has remained controversial.[17]In this study, p53 and UHRF-1 expression were investigated in gastric carcinoma and a control group. We aimed to investigate the diagnostic and prognostic value of these parameters for gastric carcinoma.     

Flow cytometric examination of p53 protein in primary tumors and metastases to the liver and lymph nodes of colorectal cancer

PURPOSE AND METHODS: To confirm prognostic significance of overexpression of p53 in cases of colorectal cancer, expression of p53 protein was examined by flow cytometry in 113 cases of colorectal cancer and its metastasis to the liver and lymph nodes. RESULTS: Overexpression of p53 was found in 44 (39 percent) of the 113 primary tumors. There were no significant correlations among the level of p53 protein in the primary tumor, clinicopathologic features, and prognosis of colorectal cancer. Overexpression of p53 protein was detected in 72 percent (18/25) of liver metastases and in 40 percent (10/25) of lymph node métastases. Frequency of samples that were positive for p53 was significantly higher for liver metastases than for primary tumors and lymph node metastases (P<0.01). By comparing overexpression of p53 in primary tumors with that in corresponding secondary tumors, a decrease of more than 5 percent in the fluorescence index, compared with primary tumor, was not found in liver metastasis but was found in 20 percent of lymph node metastases. Incidence of cases with lower level expression of p53, compared with primary tumor, was significantly higher in lymph node metastases (32 percent) than in liver metastases (8 percent;P<0.05). CONCLUSIONS: From these results, it seems possible that overexpression of p53 may not be a good prognostic indicator of colorectal cancer and may be influenced by environments of the tumor.Presented at the meeting of the Japanese Gastroenterological Surgery, Fukui City, Japan, July 20 and 21, 1995.     

Mutated p53 protein expression and proliferative activity in advanced gastric cancer.

BACKGROUND/AIMS: When the DNA of cells is damaged, wild-type p53 protein induces the expression of p21 (Waf1/Cip1/Sdi1), and regulates the progression of the cell cycle by inducing G1 arrest. Thus, wild type p53 or p21 protein negatively regulates cancer cell proliferation. However, in tumor with loss of expression of functional wild-type p53 protein by mutation or allelic deletion of the gene for p53, whether the proliferative activity of cancer cells might be accelerated or not is unclear. In this study, we investigated the correlation between the level of expression of mutated p53 protein and the proliferative activity of cancer cells in advanced gastric cancer. METHODOLOGY: Ninety-seven samples from patients with gastric cancer that had invaded the serosa without lymph node metastasis (t3, n0, stage II) were investigated by immunohistochemical staining with a monoclonal antibody against p53 and against p21, and with the monoclonal antibody Ki-67. DNA ploidy patterns were analyzed by flow cytometry. The immunoreactivity against p53 and the proliferative activity of cancer cells were scored in terms of a labeling index (LI; percentage of immunostained cells) in each case. Moreover, the prognostic values for 93 surviving patients were evaluated by univariate and multivariate analysis. RESULTS: The mean p53 LI was 24% (range: 0-82.4%) and the mean Ki-67 LI was 23.1% (range: 0-70.7%) in 97 tumors. The expression of p21 protein was detected in 30 of 97 tumors (30.9%) and DNA aneuploidy was detected in 36 of 97 tumors (37.1%). There was significant correlation between the p53 LI and the Ki-67 LI (r = 0.61, t = 7.456, p < 0.001) in 97 tumors. Although, no significant difference was detected, the mean p53 LI (18.3%) of 30 tumors with expression of p21 protein was lower than that of 67 tumors without expression of p21 protein (26.6%, p = 0.096). However, no significant correlation between expression of p21 protein and Ki-67 LI was observed. The p53 LI was not an independent prognostic factor in 93 surviving patients by multivariate survival analysis (p = 0.069). However, the 5-year survival rate of 50 patients with a low level of p53 LI (p53 LI (< or = 10%, 78.3%) was significantly better than that of 43 patients with a high level of p53 LI (p53 LI > 10%, 62.1%, p = 0.045). CONCLUSIONS: Accumulation of mutated p53 protein might suppress the expression of p21 protein in gastric adenocarcinoma, and cancer cells with overexpression of mutated p53 protein might have a high proliferative activity.     

Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa.

Abnormalities of the tumour suppressor gene p53 have been shown in approximately 60% of advanced gastric adenocarcinomas and it has been suggested that the immunohistochemical finding of increased p53 expression is a prognostic marker in gastric cancer. No studies of early (T1) tumours have been reported. Over expression of p53 protein in 95 early gastric carcinomas and in adjacent mucosa was investigated using immunohistochemistry with antibody CM1. Thirty five per cent of the tumours were positive. The frequency of p53 positivity in tumours of tubular histological type (46%) was significantly higher than that in signet ring tumours (10%) (p = 0.006), and neoplasms that invaded deeply into the submucosa were more frequently positive (45%) than others (30%). Five of eight (62%) T1 tumours with lymph node metastases showed immunoreactive p53. In signet ring tumours, immunopositivity correlated with the frequency of DNA aneuploidy. p53 Over expression was also found in 15% of 26 examples of high grade dysplasia in mucosa adjacent to invasive tumours. No positivity was found in intestinal metaplasia or in normal mucosa. The findings show that immunocytochemically demonstrable over expression of p53 correlates with other morphological markers of aggressiveness in T1 gastric adenocarcinoma. The increasing frequency of p53 immunoreactivity in the sequence of high grade dysplasia-->early gastric cancer-->advanced gastric cancer supports the view that abnormalities of p53 are related to tumour progression in gastric carcinogenesis.     

Allelic Loss of Chromosome 2p21-16.3 is Associated with Reduced Survival in Sporadic Colorectal Cancer

Background: Since allelic loss of genes involved in the development of colorectal cancer could serve as prognostic markers, we examined the correlation between loss of markers linked to the hMSH2/hMSH6 (2p21-16.3), hMLH1 (3p21.3), APC (5q21-22), p53 (17p13.1) and DCC (18q21.3) loci and survival in a series of 64 consecutively collected colorectal cancers. Methods: The association between allelic loss and survival was analysed by univariate and multivariate tests to identify independent variables of survival. Results: Loss of chromosome 2p21-16.3 reduced the overall 5-year survival from 52% to 15% (P = 0.0003). The prognostic significance was evident in patients with Dukes' A + B as well as Dukes' C tumours. A multivariate analysis comparing Dukes' staging, age at diagnosis, tumour localization, sex, loss of chromosome 2p21-16.3, 3p21.3, 5q21-22, 17p13.1 or 18q21.3 and microsatellite instability showed that only Dukes' staging (hazard ratio 3.0; 1.4-6.5 with 95% confidence interval, P = 0.0065) and loss of 2p21-16.3 (hazard ratio 6.2; 2.3-16.8 with 95% confidence interval, P = 0.0006) were independent variables of survival. Loss of 2p21-16.3 was, moreover, associated with increased loss of the other tumour suppressor loci (P = 0.012). Conclusions: The results show that loss of 2p21-16.3 is an independent indicator of survival in patients with colorectal cancer.     

Co-mutation of p53, K-ras genes and accumulation of p53 protein and its correlation to clinicopathological features in rectal cancer

AIM: To determine bhe accuracy of p53 gene mutations predicted by overexpression of p53 protein immunohistochemically,and to investigate the co-mutation of p53 and K-ras genes in rectal cancer and its effect on promoting malignant biologic behaviors of tumors.METHODS: Ninety-seven specimens of rectal cancer were surgically resected in our hospital from August 1996 to October 1997. The hot mutation areas of p53 gene (in exons 5-8) and K-rasgene (in codon 5/12 and 13) were detected with polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), and overexpression of p53 protein was detected with immunohistochemistry (IHC) in the 97 specimens of rectal cancer. Correlation between gene mutations and tumor clinicopathologic factors was studied, and survival analysis was penfomed as well.RESULTS: There were 36 cases of p53 gene mutations in 61 p53 protein positive cases, and 21 cases of p53 gene non-mutation in 36 p53 protein negative cases respectively.The coincidence rate of p53 gene mutation by IHC method with PCR-SSCP method was 58.8% (57/97). The mutation rate of p53 gene was 52.6% (51/97), while K-ras gene mutation was observed in codons 12 and 13 in 61 cases with a mutation rate of 62.9% (61/97). Single gene mutation of p53 or K-raswas found in 32 cases. Both p53 and K-ras gene mutation were found in 48 cases. Statistical analysis showed that p53 and K-ras gene mutations were not related to the dinicopathologic factors, including tumor size, gross tumor type, histological dassification, differentiation, invasion to intestinal veins, lymphatics and nerves, invasive depth to.wall, lymph node metastasis, and Dukes‘ stages (P&gt;0.05).The survival in patients with no gene mutation, single gene mutation and both gene mutations were similar (P&gt;0.05).CONCLUSION: IHC has a certain false positive and false negative rate in detecting p53 gene mutations. Malignant biological behaviours of rectal cancer are not enhanced by p53 and K-rasgene mutations. Co-mutation of p53 and K-ras gene has neither synergic carcinogenesis-promoting effect,nor prognostic effect on rectal cancer.     

p21WAF1 protein expression determined by quantitative immunoassay in relation to non-small-cell lung cancer aggressiveness

Purpose: p21WAF1, a cyclin-dependent kinase inhibitor, is an important mediator of the cell-cycle arrest and tumor suppression induced by the protein p53. Although alterations of the p53 gene and its overexpression are frequent in most malignancies, including non-small-cell lung cancer (NSCLC), and may be associated with poor patient prognosis, the clinical utility of p21WAF1 expression in NSCLC has not been established. Methods: We have used a commercial enzyme-linked immunosorbent assay (ELISA) kit for p21WAF1 to test soluble extracts of 54 NSCLC specimens with known clinicopathological properties. Results: There was no correlation between p21WAF1 and p53 concentrations, the latter being determined by a time-resolved immunofluorometric assay developed in-house. Furthermore, p21WAF1 levels were not associated with patient age, tumor/node/metastasis (TNM) stage, lymph node metastasis, histological grade or type, or smoking history, in Mann-Whitney analysis. χ²-tests, based on cutoffs equal to the 25th, 50th, or 75th percentiles of the p21WAF1 distribution, similarly did not reveal any statistically significant associations between p21WAF1 and other clinicopathological variables. Because of the small number of patients and the median follow-up of only 18 months, a meaningful survival analysis could not be performed. Conclusion: In summary, this preliminary study suggests that ELISA-quantified p21WAF1 levels in NSCLC extracts are weaker than p53 in terms of prognostic value and do not contribute to the further subclassification of patients. Received: 22 April 1999 / Accepted: 13 July 1999     

Immunohistochemical expression of TGF-beta1, p21WAF1, p53, Ki67, and angiogenesis in gastric carcinomas: a clinicopathologic study

BACKGROUND: Transforming growth factors-beta (TGF-betas) are multifunctional polypeptides with crucial role as regulators of cellular growth and differentiation. It has been reported that TGF-beta1 plays a biphasic action on tumorigenesis thus inducing or inhibiting malignant properties of the epithelial cells. METHODS: TGF-beta1 expression was analyzed in 56 patients with gastric carcinoma by immunohistochemical methods and compared with the expression of p21, p53, and Ki67, as well as with angiogenesis. The correlation of these markers with clinicopathological parameters was also evaluated. RESULTS: TGF-beta1 expression was detected in 71% of tumors and was more frequent in adenocarcinomas of the intestinal type (p < 0.001). Positivity of p21WAF1, and p53 was observed in 32% and 51% of the tumors, respectively. A high Ki67 proliferating index was detected in 53.5% of the tumors. TGF-beta1 expression was significantly correlated with p21 expression (p < 0.001) and was inversely correlated with microvessel density. p21 expression was also higher in tumors with low proliferating index (p < 0.01). There was no apparent correlation between the expression of these markers and tumor stage, depth of invasion, or lymphnode metastases. CONCLUSION: The findings show that TGF-beta1 may be involved in the activation of the cdk inhibitor p21WAF1 in gastric adenocarcinomas, suggesting p53-independent induction of p21 in gastric cells. TGF-beta1 does not seem to contribute to the alteration of the angiogenic status of these tumors.     

Clinical significance of apoptotic index in non-small cell lung cancer: correlation with p53, mdm2, pRb and p21WAF1/CIP1 protein expression

Purpose: The aim of this study was to assess the prognostic relevance of apoptotic index (AI), considered alone or together with expression of several proteins controlling G1 check point (p53, mdm2, pRb and p21^WAF1/CIP1) in non-small cell lung cancer (NSCLC) patients. Methods: Study group included 50 NSCLC patients who underwent curative pulmonary resection. Apoptosis was detected with the use of TUNEL technique and AI was defined as the number of apoptotic cells per 1,000 tumor cells. The expression of p53, mdm2, pRb and p21^WAF1/CIP1 was assessed immunohistochemically. Results: The mean and median AI calculated for all 50 patients was 14 and 9, respectively. Patients with lower (<14) and higher (≥14) AI constituted 35 (70%) and 15 (30%) of cases, respectively. AI was not correlated with patient clinical characteristics, and expression of p53, pRb and p21^WAF1/CIP1 . However, lower AI was correlated with over-expression of mdm2 protein (P=0.04). Median survival for patients with lower and higher AI was 43 months and 22 months, respectively, and 5-year survival probability—60 and 25%, respectively (P=0.03). In multivariate analysis, the only variable associated with shortened survival was AI (P=0.03, HR=2.9, 95% CI 1.95–3.86). Conclusions: These results suggest that AI correlates with mdm2 protein expression and influences survival in NSCLC.     

p53 nuclear immunoreactivity as a predictor of response and outcome following chemotherapy for metastatic bladder cancer

p53 nuclear immunoreactivity was determined in primary bladder tumours from 50 patients who developed metastatic bladder cancer. We investigated the relationship between p53 nuclear immunoreactivity and the response and outcome following chemotherapy. p53 nuclear accumulation was detected in 48% of the primary tumours using the PAb1801 antibody in archival paraffin-embedded tissue sections. All patients received platinum-based combination chemotherapy including methotrexate for metastatic disease. The response to chemotherapy did not relate to the prevalence of p53 nuclear overexpression: 50% of the patients expressing p53 nuclear reactivity achieved a response compared to 27% of those without p53 expression (P=0.14); overall, 38% of the patients responded. The median survival after chemotherapy was 5.9 months; 8.4 months for patients with p53 nuclear reactivity compared to 5.2 months for those without (P=0.38). Multivariate analysis showed that performance status but not p53 nuclear status was an independent prognostic factor for survival following chemotherapy. The results indicate that patients with p53 nuclear immunoreactivity in the primary bladder tumour do not have a lower response rate or poorer outcome following chemotherapy for metastatic disease than do patients without p53 nuclear reactivity.     

Down-expression of tumor protein p53-induced nuclear protein 1 in human gastric cancer

AIM: Overexpression of tumor protein p53-induced nuclear protein 1 (TP53INP1) induces G1 cell cycle arrest and increases p53-mediated apoptosis. To clarify the clinical importance of TP53INP1, we analyzed TP53INP1 and p53 expression in gastric cancer. METHODS: TP53INP1 and p53 expression were examined using immunohistochemistry in 142 cases of gastric cancer. The apoptosis of gastric cancer cells was analyzed using the TUNEL method. The relationship between the expression of TP53INP1 and clinicopathological factors was statistically analyzed. RESULTS: TP53INP1 was expressed in 98% (139/142 cases) of non-cancerous gastric tissues and was down-expressed in 64% (91/142 cases) of gastric cancer lesions from the same patients. TP53INP1 expression was significantly decreased (43.9%) in poorly differentiated adenocarcinoma compared with well or moderately differentiated adenocarcinoma (81.6%). Cancers invading the submucosa or deeper showed lower positively (59.1%) compared with mucosal cancers (85.2%). Decrease or loss of TP53INP1 expression was significantly correlated with lymphatic invasion (54.3% vs 82.0% without lymphatic invasion) and node-positive patients (31.3% vs 68.3% in node-negative patients). P53 was expressed in 68 (47.9%) patients of gastric cancer, whereas it was absent in normal gastric tissues. A significant association was also observed between TP53INP1 status and the level of apoptosis in tumor cells: the apoptotic index in TP53INP1-positive tissues was significantly higher than that in TP53INP1-negative portions. Finally, when survival data were analyzed, loss of TP53INP1 expression had a significant effect in predicting a poor prognosis (P=0.0006). CONCLUSION: TP53INP1-positive rate decreases with the progression of gastric cancer. TP53INP1 protein negativity is significantly associated with aggressive pathological phenotypes of gastric cancer. TP53INP1 is related to the apoptosis of gastric cancer cells. The decreased expression of the TP53INP1 protein may reflect the malignant grade of gastric cancer and is regarded as an adverse prognostic factor.     

Low presence of <Emphasis Type="Italic">p53</Emphasis> abnormalities in <Emphasis Type="Italic">H. pylori</Emphasis>-infected gastric mucosa and in gastric adenocarcinoma

Background: Alterations of the p53 gene and/or its abnormal protein accumulation have been observed in gastric cancer and preneoplastic lesions. Our aim was to assess possible associations between different H. pylori strains and p53 abnormalities in patients with dyspepsia and with gastric cancer. Methods: Seventy-five dyspeptic patients and 40 patients with gastric adenocarcinoma entered the study. H. pylori status was determined by the rapid urease test, histology, and polymerase chain reaction (PCR) analysis. Overexpression of the p53 protein was evaluated by immunohistochemistry. Detection of p53 mutations was done by direct DNA sequencing. Results: Fifty-four of the 75 (72.0%) dyspeptic patients and 27 of the 40 (67.5%) gastric cancer patients showed H. pylori infection. Cytotoxin-associated gene (cagA)-positive strains were found in 31 of the 54 (58%) dyspeptic patients and in 25 of the 27 (92.6%) neoplastic patients. As regards vacA, s2 strains showed the highest prevalence among dyspeptic patients (24 of 54 patients; 44.4%), whereas s1 strains were more expressed among cancer patients (23 of 27; 85.2%). Among the dyspeptic patients, 1 patient with duodenal ulcer showed p53 overexpression. Three mutations were identified by DNA sequencing: one in a patient with normal endoscopic findings and two in patients suffering from gastritis. Among the neoplastic patients, 16 subjects (40%) showed p53 overexpression (9 had diffuse-type and 7 intestinal-type cancer). Four mutations (10%) occurred in patients with intestinal-type gastric cancer. No association between p53 abnormalities (overexpression/mutation) and H. pylori infection was found in either group of patients. Conclusions: These results lead us to hypothesize that H. pylori infection does not affect the p53 pattern in gastric mucosa. Moreover, mutations of the p53 gene do not seem to be a predominant event in gastric carcinogenesis, at least in our populations. Received: December 14, 2001 / Accepted: May 17, 2002 RID="*" ID="*"  These authors contributed equally to the work RID="*" ID="*"  These authors contributed equally to the work Acknowledgments. The authors would like to thank Mrs B. D'Attoma and Mrs P. Fiorente for their valuable technical assistance, and Mrs M.V.C. Pragnell, B.A., for her help in revising the English. Reprint requests to: A. Di Leo     

Prevalence of Serum p53 Antibodies against Tumor p53 Protein in Colorectal Cancer

Background: Genetic events associated to colorectal carcinoma are well characterized, but there is scanty information about this issue in Egyptian subjects. The aim of this study was to investigate tissue p53 overexpression in paraffin embedded tumor and serum p53 antibodies in colorectal cancer patients with special reference to patient outcome.Patients and Methods: The study was conducted to 135 consecutive colorectal cancer patients. The tumor p53 protein was overexpressed in 60% and serum p53 antibodies in 35%, also tumor p53 accumulation is not necessarily associated with serum p53 antibodies positive cases. Tumor p53 overexpression was more frequent in distal colorectum than in proximal tumor (63.7% vs 41%) (p > 0.05).Results: Both tumor p53 overexpression and serum p53 antibodies increased signficantly with the stage of the tumor and lymph node involvement, but not with the grade, histopathological types and other histologic parameters. After a follow-up of 5 years, in the Kaplan Meier univariate analysis the factors stage (p = 0.0004), tumor p53 immunostaining (p < 0.0001) and serum p53 antibodies (p < 0.04) had a prognostic value.Conclusion: In conclusion p53 overexpression was associated with advanced histopathological stage and a high risk of recurrence.     

P21WAF1/CIP1 expression in colorectal carcinomas is related to Kras mutations and prognosis

BACKGROUND/AIM: P21WAF1/CIP1 is a cyclin-dependent kinase inhibitor activated by p53 to produce cell cycle arrest. A consensus has not been reached concerning the prognostic value of p21WAF1/CIP1 expression in colorectal cancers. PATIENTS/METHODS: P21WAF1/CIP1 expression was determined immunohistochemically in a series of 211 cases of colorectal carcinomas, together with its relation to p53, bcl-2, cell turnover (as assessed by Ki67 expression and apoptotic counts) and the Kras gene status. The expression of p21WAF1/CIP1 was also compared with reference to clinicopathological parameters and patient survival. RESULTS: The median value for nuclear p21WAF1/CIP1 expression was 31% (interquartile range, 13-47%) and the fraction of cases considered to be high expressers (>20%) was 66%. Expression of p21WAF1/CIP1 was not associated with immunoreactivity for p53 or bcl-2, or cell turnover. P21WAF1/CIP1 high-expressing tumors were more often well differentiated (P<0.001), node-negative (P=0.037), Dukes' B (P=0.027) and Kras gene-mutated cases (P=0.04). On univariate analysis, low p21WAF1/CIP1 expressers (相似文献