Cyclooxygenase-2 and p53 expressions in endometrial cancer.

Cyclooxygenase-2 (COX-2) has been known to be related with various types of carcinoma, but we have insufficient knowledge about the association between COX-2 and endometrial cancer. Many have reported a close relationship between p53 expression and a poor prognosis in endometrial cancer, but it is unclear whether p53 is an independent prognostic factor. To clarify these uncertainties, we examined the expressions of COX-2 and p53 in endometrial cancer tissues. The study was carried on 152 endometrial cancer patients who had operation at Seoul National University Hospital. Paraffin-embedded tissue blocks were sectioned and immunostained using monoclonal anti-COX-2 and anti-p53 antibodies. Twenty-seven (17.8%) specimens stained as COX-2 positive. COX-2 positivity was more frequently observed in postmenopausal patients than in premenopausal patients (8.8% versus 25.0%; P = 0.009). However, COX-2 positivity did not show a statistically significant association with any other clinicopathologic characteristic (parity, body mass index, histotype, International Federation of Gynecology and Obstetrics stage, grade, lymph node metastasis, deep myometrial invasion, or p53 overexpression). Thirty-one (20.4%) specimens showed p53 overexpression and this was significantly correlated with an advanced stage (P = 0.001), poor differentiation (P < 0.001), lymph node metastasis (P = 0.012), and deep myometrial invasion (P < 0.001). Multivariate Cox regression analysis showed that advanced stage was an independent prognostic factor of survival, but p53 overexpression was not. COX-2 may be associated with endometrial cancer carcinogenesis during the postmenopausal period but not with tumor aggressiveness and p53 overexpression. The p53 overexpression was found to be strongly associated with endometrial cancer aggressiveness.     

Prognostic significance of cyclin E and p53 protein overexpression in carcinoma of the renal pelvis and ureter.

Cyclin E gene alteration in the cell cycle plays an important role in carcinogenesis, while p53 protein affects different phase checkpoint pathways by activating p21WAF1/CIP1 in the normal cell cycle. We immunohistochemically examined the expression of cyclin E and p53 proteins in 121 patients with transitional cell carcinoma (TCC) of the renal pelvis and ureter to determine their significance for tumour behaviour and patient prognosis. Cyclin E and p53 immunostaining of the nucleus was observed in 36 tumours (29.8%) and 35 tumours (28.9%) respectively. A significant percentage, 69.4% (25 out of 36 tumours), of the cyclin E-positive tumours exhibited simultaneous labelling for p53 (P < 0.05). Mirror-section technique was performed in five selected double-positive tumours to identify cancer cells that were nuclei positive for both cyclin E and p53. The prevalence of cases simultaneously exhibiting both cyclin E and p53 immunostaining was higher in the high-grade tumours (P < 0.01) than in the other types of tumours. Patients with TCCs coexpressing cyclin E and p53 had a significantly poorer prognosis than those expressing neither cyclin E nor p53 (P < 0.001). These in vivo findings provide evidence for cyclin E protein overexpression in TCCs intimately associated with p53 alteration and suggest that simultaneous overexpression of both cyclin E and p53 is related to tumour behaviour and poor prognosis.     

beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance.

BACKGROUND: beta-Catenin has been recognized as a critical member of the Wnt signaling pathway, and inappropriate activation of this pathway has been implicated in carcinogenesis. METHODS: To determine the clinical significance of beta-catenin in hepatocellular carcinoma (HCC), we performed mutational analysis at exon 3 of the gene, investigated the subcellular protein expression, and analyzed their clinicopathologic and prognostic significance in 60 patients with resected primary HCC. RESULTS: By direct DNA sequencing, somatic mutations of the beta-catenin gene were detected in 7 (12%) HCCs. All the mutations were found at the region (exon 3) responsible for phosphorylation and ubiquitination, therefore likely to result in stabilization of free cytoplasmic beta-catenin. Nuclear accumulation of the beta-catenin protein, similar to the response to the Wnt signal, was found in 10 (17%) HCCs and was closely associated with gene mutation (P < 0.001). In the remaining cases, nonnuclear type overexpression, that is, overexpression in the cytoplasm and/or cytoplasmic membrane, was observed in 31 (62%) HCCs, thus suggesting that the mechanisms leading to beta-catenin overexpression may be heterogeneous. HCCs with a nonnuclear type of beta-catenin overexpression were more frequently larger than 5 cm in diameter (P = 0.022) and had poorer cellular differentiation (P = 0.037), and the patients had significantly shorter disease-free survival lengths (P = 0.041). Review of the data from previous studies in HCC showed that beta-catenin mutations were more frequent in HCV-associated HCC than in HBV-associated ones. CONCLUSIONS: beta-catenin mutation and deregulation may play an important role in hepatocarcinogenesis. Nonnuclear type beta-catenin overexpression appeared to have pathologic and prognostic significance.     

Lack of prognostic significance of BCL2 and p53 protein overexpression in elderly patients with diffuse large B-cell non-Hodgkin's lymphoma: results from a population-based non-Hodgkin's lymphoma registry

The prognostic significance of age was studied in 372 patients with diffuse large B-cell non-Hodgkin's lymphoma, in relation to the prognostic factors of overexpressed BCL2 and p53 oncoprotein. Overexpression of BCL2 and p53 oncoprotein was defined when more than 50% of the tumor cells showed positive staining. The data were analyzed with respect to the age groups < 65 and > or = 65 years of age. There was a trend for BCL2 overexpression to occur significantly more often among patients older than 65 years of age (P = 0.065). Patients with BCL2 overexpression showed significantly inferior disease free survival rate, but only for patients younger than 65 years (log-rank test P = 0.0002), and the overexpression showed also an independent prognostic significance (P < 0.001). With respect to overexpressed p53 a significant difference was reached for complete remission rate (P = 0.01) and 5-year survival rate (log-rank test P = 0.04), again only for the younger age group. When the analyses were repeated for the older patients who had been treated adequately, the same lack of significance was found, both for BCL2 and p53. This study demonstrates that the negative prognostic value of overexpressed BCL2 and p53 protein is not of concern for patients older than 65 years of age. Among elderly patients the International Prognostic Index score seems the predominant risk factor for inferior prognosis.     

p53 mutation, but not p53 overexpression, correlates with survival in head and neck squamous cell carcinoma.

Survival in squamous cell carcinoma of the head and neck (HNSCC) was compared with overexpression and mutation of the p53 gene. Archival tissue from 77 tumours was analysed for protein expression using immunohistochemistry (IHC) with the monoclonal antibody Do-7, and for the presence of mutation in exons 5-8 using single-stranded conformation polymorphism (SSCP), followed by DNA sequencing in SSCP-positive cases. p53 expression was scored as high (>70% nuclei stained) in 25 (32%) tumours, as intermediate (10-70% nuclei stained) in 19 (25%) tumours and as low (<10% nuclei stained) in 33 (43%) tumours. Twelve (18%) tumours exhibited gene mutation (ten missense and two nonsense mutations) and an additional five tumours contained changes that could not result in amino acid substitution or protein truncation. There was no correlation between gene expression and mutation, mutations being equally frequent in tumours with either high (4/25), intermediate (4/19) or low protein expression (4/33). Fifty-eight patients were eligible for survival analysis. There was a strong correlation between p53 mutation and cause-specific survival; median survival among mutated cases was 12.5 months compared with >160 months among non-mutated patients (P < 0.005). There was no correlation between p53 overexpression and survival. The results suggest that p53 mutation status is an important prognostic factor in HNSCC, and that IHC analysis of protein overexpression is an inadequate measure of gene mutation in these tumours.     

Independent prognostic importance of microvessel density in endometrial carcinoma.

Angiogenesis is thought to be an important factor for tumour growth and metastatic spread, and microvessel counts may provide useful prognostic information for several tumour types. To investigate the prognostic impact of angiogenesis in endometrial carcinoma patients, the intratumour microvessel density, which was determined immunohistochemically, has been related to survival. Sixty patients with endometrial carcinoma with long (median 19 years) and complete follow-up have been studied. Patients with increased mean microvessel density (MVDmean > 68 mm2) had a significantly shorter 5-year survival compared with the rest (57% vs 90%, P = 0.004). In multivariate survival analyses, MVDmean had an independent prognostic impact (P = 0.03) when FIGO stage, histological type, histological grade as well as nuclear p53 protein expression was adjusted for. These findings indicate that intratumour microvessel density may contribute additional prognostic information to that obtained from the known risk factors and may be helpful in identifying endometrial carcinoma patients at high risk for disease progression.     

Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer.

PURPOSE: The p53 tumor suppressor gene plays a central role in cell cycle regulation and induction of apoptosis. We analyzed p53 alterations and their impact on response to chemotherapy and clinical outcome in ovarian cancer patients. EXPERIMENTAL DESIGN: One hundred seventy-eight ovarian carcinomas, snap frozen and stored at -80 degrees C, were analyzed for mutations of the p53 gene (exons 2-11) by single-strand conformation polymorphism and DNA sequencing and for p53 overexpression by immunohistochemistry (monoclonal antibody DO7). RESULTS: p53 mutations were found in 56% (99 of 178) of the tumors, and 62% of these were located in evolutionary highly conserved domains of the gene. Time to progression and overall survival were significantly shortened in patients with p53 mutations compared with wild-type p53 (P = 0.029 and P = 0.014) and patients with mutations in highly conserved domains as opposed to nonconserved domains or wild-type p53 (P = 0.010 and P = 0.007). p53 protein overexpression (>10% positively stained nuclei) was found in 62% (110 of 178). Time to progression and overall survival were shorter in cases with p53 overexpression (cutpoint, 10%: P = 0.071 and P = 0.056) but only marginally significant. Resistance to adjuvant cisplatin or carboplatin chemotherapy was significantly more frequent in patients with p53 overexpression (P = 0.001) or p53 missense mutations (P = 0.008) than patients with normal p53. CONCLUSIONS: p53 alterations correlate significantly with resistance to platinum-based chemotherapy, early relapse, and shortened overall survival in ovarian cancer patients in univariate analysis. In multivariable analysis though, p53 was not an independent prognostic factor.     

Prognostic factors in surgical stage I endometrial carcinoma

The prognostic impact of DNA ploidy, MIB-1 and p53 was evaluated in relation to clinical and histopathological features in surgical stage I endometrial carcinoma (n = 284) and in the histopathological endometrioid subgroup (n = 257). Tumour material from 284 consecutive patients was analysed regarding image cytometric DNA ploidy and the immunohistochemical MIB-1 and p53 expression. Twenty-four tumours relapsed. In univariate analysis, histopathological subgroup (endometrioid vs. non-endometrioid), grade, DNA ploidy and p53 were highly significant prognostic factors (p < or = 0.001). MIB-1 was also significant (p = 0.039). In the endometrioid subgroup only DNA ploidy and p53 were significant (p < 0.001). In multivariate analysis of the entire material, ploidy and histopathological subgroup retained their significance (p = 0.001, p = 0.004), whereas only ploidy was significant in the endometrioid subgroup (p = 0.001). DNA ploidy was the strongest predictor of relapse-free survival and the only independent prognostic factor in the endometrioid subgroup.     

Prognostic implications of molecular and immunohistochemical profiles of the Rb and p53 cell cycle regulatory pathways in primary non-small cell lung carcinoma.

PURPOSE: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non-small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. EXPERIMENTAL DESIGN: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non-small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. RESULTS: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21(Waf1) overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). CONCLUSIONS: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.     

Evaluation of prognostic-significance of p53 gene alterations in patients with surgically resected lung-cancer

Clinical significance of p53 gene alterations, as a prognostic factor, was assessed in 69 patients with surgically resected lung cancer. The p53 gene alterations (exon 5-9) were examined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method of genomic DNA. The p53 gene alterations were detected in all histological types of lung cancer, with a positive rate of 45% (31/69). In the alteration-positive group, patients in the advanced stages of III and IV were seen more frequently than in the negative group (58% vs. 21%, p<0.05). Such a difference was not observed in other parameters such as age, gender, histological type and smoking habit. The prognosis was, on a whole, poorer in the alteration-positive group than for the -negative one (5-year survival rate: 19.3% vs. 40.6%, MST: 17 months vs. 36 months), but the difference did not reach statistical significance. However, in the case of females (p<0.05), adenocarcinoma (p<0.01), early stages of I and II (p<0.05) and non-smokers (p<0.005), a significantly poorer prognosis was observed in the gene alteration-positive group than for the -negative one. These results suggest that the p53 gene alteration may be a useful prognostic factor in certain subgroups with lung resected for cancer.     

Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker

Objective Subcellularly localized (nuclear and/or cytoplasmic) survivin has various functions, and correlates with prognosis of malignant tumors. However, there have been no reports about the significance of subcellularly localized survivin in high-grade astrocytomas. The aim of the present study was to examine the relationship between prognosis and subcellular localization of survivin in high-grade astrocytoma. Methods We immunohistochemically examined the pattern of subcellular localization of survivin expression (nuclear, cytoplasmic, or both) in 51 patients with high-grade astrocytoma (19 anaplastic astrocytomas; 32 glioblastomas). We statistically examined the relationship between survivin localization and prognosis, using multivariate analysis including other clinicopathological factors (age, sex, WHO grade, extent of resection, MIB-1 labeling index, and expression of p53 and epidermal growth factor receptor). Results All specimens stained positive for survivin: localized in nucleus only (nuclear-positive group), 10 cases (20%); localized in cytoplasm only (cytoplasmic-positive group), 23 cases (45%); simultaneous expression in nucleus and cytoplasm (nuclear-cytoplasmic group), 19 cases (35%). There was no significant difference in prognosis between the nuclear-positive group and cytoplasmic-positive group (P = 0.796). However, the nuclear-cytoplasmic group had significantly shorter overall survival than the nuclear-positive group and the cytoplasmic-positive group (P < 0.0001). Conclusions We found that simultaneous expression of survivin in both the nucleus and cytoplasm is an important prognostic factor for high-grade astrocytoma. The present findings indicate that subcellular localization of survivin expression is a reliable prognostic factor for patients with this tumor.     

p53 mutations have no additional prognostic value over stage in bladder cancer.

Evidence is accumulating that the tumour-suppressor gene p53 is involved in the development of bladder cancer. Therefore we studied p53 mutations in 47 bladder cancers obtained from 45 patients using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. Eight out of 24 invasive tumours appeared to have a p53 mutation, while no p53 mutations were found in the superficial tumours. All the p53 mutations were found in grade 3 tumours. The tumours with altered p53 showed a higher frequency of allelic loss (FAL) than the tumours without a mutation (55.8% vs 21.1%, P < 0.05, chi 2 test). This increase in FAL suggests a correlation between p53 mutations and genetic instability. A significant correlation between mutated p53 and poor survival in the whole group studied was found (P < 0.001, log-rank test). However, within the group of muscle-invasive tumours the occurrence of p53 mutations had no additional prognostic value. Therefore, even though p53 mutations were found in aggressive tumours, the clinical usefulness of its detection seems limited. Nevertheless, these results imply that p53 is involved in the clinical behaviour of bladder cancer; its role in the progression of superficial cancer to invasive disease merits further attention.     

Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma

BACKGROUND: Inactivation of the tumor suppressor gene PTEN/MMAC1/TEP1, located on chromosome 10q23, is a common event in advanced stages of diverse human malignancies. However, the prognostic role of PTEN expression in patients with hepatocellular carcinoma (HCC) has not been characterized. METHODS: One hundred five resected specimens were collected from patients with HCC. Expression levels of PTEN and p53 in clinical samples were analyzed by immunohistochemistry. RESULTS: Immunohistochemical analysis of 105 HCC tissue specimens revealed that decreased or absence of PTEN immunostaining was found in 43 specimens (40.9%). Reduced PTEN expression levels were correlated with increased tumor grade (P = 0.017), advanced disease stage (P = 0.016), and elevated serum alpha-fetoprotein (alphaFP) levels (P = 0.001). Kaplan-Meier analysis indicated that patients with reduced PTEN levels had shorter overall survival (P = 0.001) and higher recurrence rates (P = 0.0007) compared with patients who had intact PTEN expression. Examining p53 expression unveiled an inverse correlation between p53 overexpression and reduced PTEN expression in patients with HCC (P = 0.004). In addition, patients with p53 overexpression had shorter overall survival compared with patients who were without p53 overexpression (P = 0.0014). Univariate and multivariate analyses revealed that reduced PTEN expression was an independent prognostic factor for survival in patients with HCC. CONCLUSIONS: The current study demonstrated that reduced PTEN expression levels are involved in the pathogenesis of HCC. Moreover, decreased PTEN expression was correlated with tumor progression, high alphaFP levels, p53 overexpression, and poor prognosis in patients with HCC.     

The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma

BACKGROUND: The prognostic significance and nature of p53 dysfunction in ovarian carcinoma is unclear. The relation between p53 overexpression, p53 mutations, and their effects on overall survival in primary ovarian carcinoma is explored. METHODS: Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mutations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations on overall survival were assessed. RESULTS: Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in nearly 100% of advanced stage ovarian carcinomas. These include null mutation, nonresponsive p53 (wild-type [wt] p53 sequence, DO7 negative), sequestration (wt p53 sequence, DO7 positive), and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9% of the 122 Stage III or IV (International Federation of Gynecology and Obstetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The nonresponsive p53 and null sequence tumors grouped together as functionally null convey the worst prognosis relative to missense mutations in a univariate model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis. CONCLUSIONS: Sequestration of wt p53 is unique to advanced stage ovarian carcinoma. Functionally null p53 represents an independent molecular predictor of compromised survival.     

Prognostic Significance of p53 and ras Gene Abnormalities in Lung Adenocarcinoma Patients with Stage I Disease after Curative Resection

We investigated the prognostic significance of p53 gene abnormalities and ras gene mutations in patients with curatively resected stage I lung adenocarciiioma. Formalin-fixed and paraffin-embedded tissues were obtained from 30 patients who had undergone curative resection for stage I lung adenocarciiioma. Abnormalities of the p53 gene were detected using polymcrasc chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analysis and immunohistochemistry and ras mutations were detected using PCR-restriction fragment length polymorphism (RFLP) analysis. Both univariate and multivariate analyses were performed to assess the relationship between the presence of abnormalities of these genes and the patients'disease-free survival. Eleven tumors (37%) had mutated p53 sequences and 11 (37%) showed p53 overexpression. A total of 15 tumors (50%) had p53 gene abnormalities and the concordance rate was 73%. Seven tumors (23%) showed mutated ras sequences. The univariate analysis revealed that the disease-free survival of patients with any p53 abnormality was shorter than that of those without abnormalities ( P= 0.02, generalized Wilcoxon test), and survival of those with p53 protein overexpression was more significantly shorter ( P= 0.003, generalized Wilcoxon test). Multivariate analysis using the Cox proportional hazards model indicated that the presence of p53 abnormalities was a significantly ( P =0.01) unfavorable prognostic factor. There was no significant correlation between the presence of ras mutation and survival. These results suggest that analysis of the p53 gene may be helpful for the selection of high-risk patients for clinical trials of adjuvant therapy for stage I lung adenocarcinoma.     

Methylation of hMLH1 in a population-based series of endometrial carcinomas.

Microsatellite instability (MSI) is a characteristic feature of hereditary nonpolyposis colorectal cancer and is also observed in sporadic colorectal and endometrial cancers. Alterations in the mismatch repair genes hMLH1 and hMSH2 are important for the development of MSI. It has recently been demonstrated that hypermethylation of the hMLH1 promoter region is associated with MSI and appears to be a common mechanism for gene inactivation. For endometrial carcinoma, however, previous studies have been relatively small and have not been population based. We therefore wanted to assess the frequency and prognostic significance of hypermethylation of the hMLH1 and hMSH2 genes in conjunction with hMLH1 protein expression in a prospective and population-based series of endometrial carcinoma patients with known MSI status and complete follow-up. A total of 138 patients were studied, and methylation of hMLH1 was found in 23% of tumors with conclusive results, whereas methylation of hMSH2 was seen in only 1% of tumors. Methylation of hMLH1 was significantly correlated with MSI (P < 0.001). Loss of nuclear staining of hMLH1 protein was seen in 14% of the cases and was significantly correlated with hMLH1 methylation and MSI (P < 0.001). Normal expression of hMLH1 was seen in all of the unmethylated tumors (100%). Of the 14 MSI-positive tumors that were also methylated, all but 1 (93%) showed a loss of nuclear expression of hMLH1. None of the tumors with loss of hMLH1 expression or hMLH1 methylation were aneuploid (P for both < or = 0.05), and loss of hMLH1 expression and hMLH1 methylation was significantly correlated with lack of p53 overexpression (P for both < or = 0.05). Nuclear hMLH1 staining and hMLH1 methylation did not significantly influence survival. In conclusion, hMLH1 methylation was common and was significantly correlated with loss of hMLH1 protein expression, MSI, diploid tumors, and lack of p53 overexpression. In contrast, hMSH2 methylation was infrequent in this prospective and population-based series of endometrial carcinomas.     

Clinicopathological characteristics of p53 overexpression in endometrial cancers

Using immunohistochemical methods, we analyzed the association between nuclear p53 overexpression and various clinico-pathological parameters in patients with endometrial cancers. Formalin-fined and paraffin-embedded tissue sections from 139 cases of endometrial cancer (endometrioid type, 126; serous papillary type, 12; and clear-cell type, 1) were stained with anti-p53 monoclonal antibody (MAb) DO7. Overexpression of p53 was associated with high malignant potential, including extensive muscular invasion, advanced surgical stage, high histological grade, serous papillary type and a personal history of cancer. Lymph-node metastasis was also related to p53 overexpression with marginal significance. Survival curves determined by the Kaplan-Meier method and univariate analysis showed p53 overexpression to be associated with a poor outcome in endometrial cancer patients. However, multivariate analysis using the stepwise Cox proportional-hazard model showed that whereas lymph-node metastasis, a personal history of cancer and muscular invasion were related to poor survival rates, p53 overexpression was not. Consequently, p53 overexpression itself does not appear to be an independent prognostic factor in endometrial cancer, although a still larger sample of patient material would be required to assess this issue definitively. © 1994 Wiley-Liss, Inc.     

Disrupted p53 function as predictor of treatment failure and poor prognosis in B- and T-cell non-Hodgkin's lymphoma.

Mutation of the p53 gene has been associated with treatment failure and poor outcome in various malignancies. It has been suggested that immunohistochemical analysis of p53 and p21Waf1, a downstream target, can be used to screen for p53 gene mutations. We determined the value of immunohistochemical screening for p53 gene mutations as a prognostic marker in a population-based group of B- and T-cell non-Hodgkin's lymphomas (NHLs). On the basis of p53 gene mutation status and immunohistochemically detected p53 and p21Waf1 expression in 34 lymphomas, we established an immunophenotype (delta p53) correlating with p53 gene mutation. The immunohistochemical analysis was extended to encompass 199 lymphomas from a population-based registry and was correlated with clinical parameters. Delta p53 showed 100% concordance with p53 gene mutation and was detected in 42 cases (21%). Multivariate analysis of advanced stage lymphomas showed that delta p53 was independently associated with treatment failure (relative risk, 3.8; P = 0.001). Delta p53 predicted poor survival when analyzing all patients (P = 0.0001), as well as B-cell (P = 0.04) and T-cell NHL (P = 0.000002). In multivariate analysis, delta p53 (relative risk, 2.2; P = 0.001) maintained prognostic significance. The impact on prognosis of delta p53 was highly significant in the low-intermediate-risk group (P = 0.00002). Comparing survival of the aggressive lymphoma patients in this group showed that the 8 delta p53 patients died within 1 year, whereas the median survival of the 28 non-delta p53 patients was 36 months. These results suggest that immunohistochemically assessed p53 status may predict treatment response and outcome in B- and T-cell NHL patients.     

p53 correlates with improved survival in patients with esophageal adenocarcinoma

Esophageal adenocarcinoma is a virulent malignancy that is rapidly increasing in incidence. Overexpression of p53, a tumor-suppressor gene with prognostic significance in many malignancies, has not been adequately evaluated in this disease. The purpose of this study was to evaluate the pattern and importance of p53 protein accumulation in patients with esophageal adenocarcinoma. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tissue from 24 patients, all of whom had early stage disease. Nineteen of 24 patients underwent surgery, and 16 had complete tumor resection. p53 oncoprotein immuno-reactivity was demonstrated in 50% (12/24) of patients overall and 50% (8/16) of patients undergoing esophagectomy. p53 overexpression was more common in patients with well-differentiated tumors (P=0.07). The tissue surrounding tumor stained positive for p53 in six patients, four of whom had no evidence of Barrett's epithelium. Among the 16 patients who underwent esophagectomy, those whose tumors demonstrated p53 overexpression had a longer overall (28 vs. 13.5 months) and disease-free (24.3 vs. 13 months) median survival. The difference in disease-free survival was significant (P=0.05). Our findings suggest that p53 overexpression may serve as a marker of improved survival in patients with esophageal adenocarcinoma. © 1995 Wiley-Liss, Inc.     

Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data

BACKGROUND: Overexpression of p53 has been associated with poor survival following breast carcinoma. BRCA1 interacts biochemically with p53 and may also contribute to poor outcome when constitutionally mutated. The joint effect of both abnormalities has not been studied. The primary objective of this study was to assess the impact of germline BRCA1 mutations and p53 overexpression on survival after 10 years of follow-up. METHODS: A historical cohort of Ashkenazi Jewish women 65 years or younger with invasive breast carcinoma was tested for BRCA1 founder mutations. p53 overexpression was assessed by immunohistochemistry. Clinicopathologic information was obtained by chart review. RESULTS: In total, 278 women were analyzed. On univariate analysis, p53 overexpression (n = 63) was prognostic for worse overall survival (relative risk [RR] 2.6, P = 0.001) whereas BRCA1 germline mutations (n = 30) were of borderline significance (RR 1.9, P = 0.052). In the lymph node-negative subpopulation, BRCA1 mutation status conferred a higher mortality on univariate (RR 5.6, P < 0.001) and multivariate (RR 3.5, P = 0.03) analyses. There was a trend in favor of a worse prognosis for women who carried a germline BRCA1 mutation and whose tumor overexpressed p53. When compared with noncarriers, BRCA1 mutation carriers had a worse overall survival if they did not receive adjuvant chemotherapy (RR 3.3, P= 0.01) or adjuvant hormonal therapy (RR 2.3, P = 0.02). CONCLUSIONS: Germline BRCA1 mutations and p53 overexpression carry a negative prognosis that is not additive to known prognostic factors. Given the experimental sensitivity of BRCA1-mutated cells to chemotherapy, the worse survival among BRCA1 mutation-carrying lymph node-negative breast carcinoma patients may be partly explained by the significantly lower proportion of lymph node-negative patients who received adjuvant chemotherapy (P < 0.001).