Pretreatment p53 nuclear overexpression as a prognostic marker in superficial bladder cancer treated with Bacillus Calmette-Guérin (BCG)

INTRODUCTION: Altered p53 gene product correlates with the stage and grade of bladder tumor, but its value as a predictor of BCG response has been disappointing. In order to revisit the prognostic value of pretreatment p53 nuclear overexpression for the BCG response, we studied a large cohort of consecutive patients with superficial bladder cancer treated with BCG. METHODS: From 1988 to 2001, 102 patients with a history of multifocal, recurrent, and/or high-risk papillary transitional cell carcinoma or carcinoma in situ, were treated for the first time with BCG. p53 immunostaining was performed on paraffin-embedded tissues using monoclonal antibody DO7 and an automated immunostainer. Special attention was paid to the conditions of tumor fixation. p53 overexpression was defined as more than 20% tumor cells with p53-stained nuclei. RESULTS: Immunostaining was significantly higher for Ta/T1 G3 +/- Cis (p < 0.001), tumoral substage T1b (p = 0.001), grade 3 (p = 0.0001), and Cis (p = 0.002). Times to recurrence, progression and cancer death were shorter among patients with p53 overexpression (p = 0.03; p < 0.0001; p = 0.0003). In multivariate analysis, p53 overexpression was an independent predictor of recurrence (p = 0.0003) [RR = 0.15; 95%CI, 0.06 to 0.42]. CONCLUSION: Pretreatment p53 nuclear overexpression in superficial bladder tumors is associated with a high risk of disease recurrence, progression and cancer death after BCG therapy. Applying antibody DO7 with an automated immunostainer and stringent fixative conditions, p53 nuclear immunostaining yields clinically relevant information and may be a useful tool for selecting patients with superficial bladder cancer who might be resistant to BCG.     

Detection of p53 tumor-suppressor-gene protein in bladder tumors and prostate cancer: possible clinical implications

Summary For a variety of human malignancies such as breast cancer and cancer of the prostate, p53 oncoprotein overexpression indicating an alteration of the p53 tumorsuppressor gene has been described as a prognostic factor for a poor clinical outcome. To investigate the overexpression of p53 oncoprotein in transitional-cell carcinoma of the bladder, 58 bladder cancer specimens of different clinical stages and histological grades were investigated using an immunohistochemical approach. A correlation between p53 positivity and tumor stage was observed, with an increase from 38.5% of superficial (T_a) tumors to 83.3% of muscle-invasive (T₃/T₄) tumors staining positively for p53 oncoprotein. Furthermore, an increase from 46.7% of G₁ tumors to 75% of G₃ tumors was observed. In 22 of 25 (87%) informative patients the results of the immunohistochemical staining could be verified by the determination of p53 mutations as detected by polymerase chain reaction (PCR)-directed analysis of restriction-fragment-length polymorphisms (RFLP). To determine the prognostic value of p53 immunohistochemistry for the clinical course of superficial bladder cancer, the overexpression of p53 oncoprotein was investigated in 41 patients with superficial bladder tumors (T₁) undergoing complete transurethral tumor resection. The detection of p53 protein was correlated with further clinically important variables such as sex, age, histological grading, former instillation therapy, and immunohistochemical determination of the proliferation rate by staining for PCNA (proliferating-cell nuclear antigen; monoclonal antibody PC10). After a median follow-up period of 54 months, 7 of 8 patients for whom more than 20% of cells stained positively for p53 had disease progression as compared with only 1 of 33 patients who were negative for p53 detection (P<0.01; chi-square test). For other urological tumors such as prostate cancer, the results of immunohistochemistry are more difficult to interpret and require definite confirmation on the DNA level.     

p53 Gene mutations in superficial bladder cancer

OBJECTIVES: To assess the presence of p53 gene mutations in superficial tumors of the urinary bladder (transitional cell carcinoma) and their relationship to classic prognostic factors for cancer recurrence and progression. To analyze the implication of these mutations on the P53 protein structure. MATERIALS AND METHODS: Observational, cross-sectional study of 90 consecutive patients, 60 with superficial transitional cell carcinoma (pTa and pT1) and 30 without neoplastic disease (control group). Samples of bladder tumor and control normal mucosa were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) to detect p53 mutations in exons 5-9. Automatic sequencing was used to characterize the mutations and their effect on the P53 protein was analyzed. Bivariate analysis was used to assess the association with other prognostic factors. RESULTS: PCR-SSCP found no mutations in any control group patient, whereas 38.3% of patients with superficial transitional cell carcinoma had one or more mutations in the exons analyzed. Thirty mutations were sequenced; all were point mutations and 86.67% were considered relevant for the P53 structure. A total of 93.3% of the mutations were located in highly conserved regions and 73.3% in mutational hot spots. The highest cell differentiation grades and pT1 stage were associated with a higher incidence of p53 gene mutations. Previous recurrences and other tumor-related histological variables were not associated with a higher percentage of mutations. CONCLUSION: Mutations at p53 did not appear in healthy bladder mucosa and were significantly more frequent in pT1 and high-grade (G-II and G-III) tumors. All mutations detected were point mutations and most caused considerable P53 structural abnormalities, implying major repercussions on P53 function. These data suggest that certain p53 mutations may have prognostic value, even though they were not associated with other classic recurrence and tumor progression parameters. Future analyses of the progress of patients with superficial bladder transitional cell carcinoma and mutated p53 will help clarify this aspect.     

Prognostic implications of p53 gene mutations in bladder tumors

PURPOSE: Alterations in the p53 gene related to neoplastic progression were studied in tumor tissue samples from patients with transitional cell carcinoma and correlated with classic staging parameters. On this basis, biological characterization of the tumor was performed to establish subgroups of patients at high risk and those with a more favorable prognosis. MATERIALS AND METHODS: This observational, analytical and cross-sectional study included 115 patients divided into 4 homogeneous groups of 1-control, 2-primary superficial transitional cell carcinoma, 3-recurrent superficial transitional cell carcinoma, and 4-infiltrative transitional cell carcinoma. DNA was obtained from tumor tissue samples and polymerase chain reaction-single strand conformational polymorphism analysis was performed on exons 5 to 9 of the p53 gene. Samples showing mutations were submitted to automatic sequencing. Statistics included bivariate analysis and logistic regression. RESULTS: Of the tumors the 63.8% were superficial and 37.2% were infiltrative transitional cell carcinoma. Of the infiltrative tumors 23.5% (8 of 34) resulted from recurrent transitional cell carcinoma. Mutations were found in samples from 46.8% of patients, all with bladder tumors. There was a trend toward increasing appearance of mutations as the size of the tumor, number of tumor implants, degree of dedifferentiation and stage of local infiltration increased. The presence of mutations in p53 was 2.5 times greater in infiltrative tumors than in low stage and 4.3 times greater in moderate to high grade than in low grade tumors. All mutations found were point mutations and 79.25% provoked severe alterations in protein structure. CONCLUSIONS: Mutations in the p53 gene are mainly point mutations that aggregate in hot spots, and provoke genetic instability and substantial changes that alter p53 function, implying a trend to tumor progression and dissemination (with a greater proportion of mutations in high stage high grade tumors). Since a large percentage of bladder tumors are under staged, analysis of p53 gene mutations could be useful as a factor for prognosis and therapeutic decisions.     

Correlation between p53 mutations and HPV in bilharzial bladder cancer

Alterations of the p53 tumor suppressor gene are the most common genetic changes detected in human cancers as well as in papillary and invasive bladder cancer. Several studies have demonstrated an association between HPV infection and urological malignancies. In the present work, the p53 gene status was studied together with the frequency of HPV in 99 cases of Bilharzial bladder cancer [BBC] in Egypt and both were correlated to the clinicopathological features of the patients. SSCP and sequencing were used to screen the p53 gene for mutations at exons 4-10 and IHC was performed to detect protein overexpression. PCR was used for detection and typing of HPV-DNA in tumor samples. p53 mutations were detected in 33.3% of the studied cases whereas protein overexpression was detected in 35.6% of the cases. The highest concordance rate was observed in cases harboring mutations at exon 4 [87.5%]. Bilharzial infestation was obvious in 72.2% of the cases that showed mutations. Exon 8 showed the highest rate of mutation [32%] followed by exons 4 and 5 [22% each]. The commonest mutational event was G:C transversion [15/50] especially at CpG dinucleotides. A mutational hot spot was detected at exon 4, codons 72-73. HPV-DNA was detected in 48.97% of the cases the majority of which [64.6%] were of type 16. Significant correlation was found between p53 mutation and the pathological stage as well as p53 overexpression and tumor grade. Our results demonstrate that the mutational spectrum in BBC is different from that of bladder cancer in Western countries in many aspects and suggest an etiological role of HPV in this type of neoplasm. However, both HPV infection and p53 gene abnormalities may contribute to Bilharzial bladder carcinogenesis in an independent way.     

p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer

Cholangiocarcinoma occurs frequently in patients with primary sclerosing cholangitis (PSC). We evaluated the incidence and prognostic significance of p53 protein overexpression and K-ras gene mutations in patients with biliary tract cancer and PSC. p53 protein expression was determined in specimens from 12 patients with biliary tract cancer, using the antibody, D07. K-ras mutations were detected using DNA sequencing and a mutation ligation assay. Accumulation of p53 protein was detected in 6 of 12 tumors (50%). K-ras mutations were detected in 4 of 12 tumors (33%). Overall survival in patients with p53-negative tumors was significantly longer (P < 0.05) than that in patients with p53-positive (mutant) tumors. Similarly, overall survival was significantly longer (P < 0.05) in the absence of a K-ras mutation than in patients with a tumor containing a K-ras mutation. Mean interval from the time of diagnosis of PSC until the diagnosis of biliary tract cancer was significantly shorter (P < 0.05) in patients with p53 overexpression than in those patients without p53 overexpression (2 versus 47 months). p53 overexpression and K-ras mutations occur commonly in patients with PSC and biliary tract cancer and are associated with a shortened survival. Patients with longstanding PSC are less likely to have these genetic alterations and may have a better prognosis. Received: September 24, 1999 / Accepted: June 6, 2000     

Relevance of p53 gene alterations for tumor recurrence in patients with superficial transitional cell carcinoma of the bladder

PURPOSE: The prognostic relevance of p53 protein accumulation in muscle-invasive bladder carcinoma is well documented, but the prognostic relevance of p53 alterations in superficial bladder tumors remains uncertain. Immunohistochemical data are divergent, possibly because of the use of nonstandardized techniques. We therefore investigated the relevance of p53 gene point mutations and loss of heterozygosity (LOH) for tumor recurrence. The results of this molecular analysis were compared with accumulation of the p53 protein as shown by immunohistochemistry. MATERIAL AND METHODS: Representative tumor tissue was selected and microdissected from 40 patients (pTa, 18 patients; pT1, 22 patients; grade I, 7 patients; grade II, 28 patients; grade III, 5 patients). Polymerase chain reaction (PCR) was carried out with exons 5-8. All PCR products were screened for p53 mutations with temperature-gradient gel electrophoresis (TGGE). When mobility shift was observed, direct nucleotide sequencing was performed. Detection of LOH was performed with nonradioactive microsatellite analysis using three markers (TP 53, D17S513 and D17S786) on chromosome 17p. Immunohistochemistry was performed with the DO 7 antibody. Tumor samples with p53 accumulation of 5% or more positive nuclei were classified as positive. Univariate analysis for disease-free survival was performed using Kaplan-Meier analysis and the log-rank test. RESULTS: TGGE and direct sequencing detected mutations in 10 of 40 patients (2 of 18 pTa and 8 of 22 pT1 patients). LOH was detected in 11 patients. Both a mutation and LOH were detected in 3 patients. p53 immunohistochemistry detected at least 5% positive nuclei in 28 of 40 patients (70%). After a median follow-up of 26 months 14 patients suffered disease recurrence. Whereas disease-free survival did not correlate with a mutation (p = 0.77, log-rank test), LOH (p = 0.2) or a mutation in combination with LOH (p = 0.23), a positive p 53 immunoreaction was significantly associated with short disease-free survival (p = 0.009). CONCLUSION: Despite the relatively high percentage of patients with p53 gene alteration in this population no significant correlation between the detection of molecular alteration and disease recurrence could be found. We conclude that, in contrast to immunohistochemical accumulation, gene alterations play only a minor role in tumor recurrence of p53 in patients with superficial transitional cell carcinoma of the bladder, and that immunohistochemical accumulation of the p53 protein has to be explained by mechanisms other than gene mutations.     

Association of positive serum anti-p53 antibodies with poor prognosis in bladder cancer patients

AIMS: To assess the association of serum anti-p53 antibodies and overexpression of tumor p53 protein with survival and prognostic factors in patients with urinary bladder tumors. METHODS: Seventy-six patients with transitional cell carcinoma of the urinary bladder were assessed prospectively (Ta, 18; T(1), 30; > or =T(2), 28). Serum anti-p53 antibodies were detected by enzyme-linked immunosorbent assay. Tumor p53 gene overexpression was assessed by immunohistochemical staining. The mean follow-up time was 34 months. RESULTS: Serum anti-p53 antibodies were positive in 25 patients (33%). Overexpression of tumor p53 protein was positive in 41 patients (54%). There was an association between the presence of serum anti-p53 antibodies and tumor p53 gene overexpression (P = 0.001). The total survival of the patients with positive serum anti-p53 antibodies was shorter than the patients with positive tumor p53 gene overexpression (P < 0.001, P = 0.344, respectively). In the multivariate survival analysis, both tumor stage and serum-p53 antibodies were found to be independent survival predictors (P = 0.004, P = 0.006, respectively). CONCLUSION: Serum anti-p53 antibody positive tumors had a worse prognosis than those with negative serum levels, regardless of the p53 status of the tumor.     

p53 expression in correlation to clinical outcome in patients with renal cell carcinoma

OBJECTIVE: The aim of this study was to evaluate the role of p53 as prognostic factor in renal cell carcinoma (RCC) and its relation to clinicopathological factors. MATERIAL AND METHODS: The nuclear accumulation of p53 protein was determined by immunohistochemical analysis in RCC specimens from 90 patients and was correlated with clinical stage, grade, DNA ploidy, S-phase fraction and cancer-specific survival. RESULTS: p53 overexpression was observed in 17 of 90 (19%) tumours. There was a significant correlation to stage (p = 0.016) and grade (p = 0.020) but not to DNA ploidy or S-phase. Patients with high p53 immunoreactivity had shorter cancer-specific survival (p = 0.003) than those with normal p53 protein expression. This difference was found in papillary and chromophobe tumour types (p < 0.0001) but not in conventional RCC. CONCLUSIONS: In patients with RCC, significant correlations between p53 protein expression and tumour stage, grade and survival time were observed. For patients with chromophobe and papillary tumour types, but not in conventional RCC, p53 immunoreactivity gave prognostic information, suggesting that the prognostic differences in p53 immunoreactivity might be due to disparate genetic abnormalities in the different RCC types.     

Inactivation of tumor suppressor genes and deregulation of the c-myc gene in urothelial cancer cell lines

Recent investigations have demonstrated p53 and Rb alterations in a subset of transitional cell carcinoma (TCC). Further genetic changes during tumor progression include overexpression of the c-myc gene in a significant number of mainly invasive bladder tumors. To study the possible interactions between these genes in TCC, urothelial cancer cell lines were chosen as an in vitro model. Expression and mutation of p53 was studied in 15 bladder cancer cell lines by immunocytochemistry, Western blot, polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis and direct sequencing of double stranded PCR products of exons 4, 5, 7 and 8 of genomic DNA. C-myc expression and gene structure were studied using Northern and Southern blot techniques. Rb protein expression was analyzed by Western blot. Twelve of 15 cell lines showed either p53 mutations or abnormal protein expression. Consistent with previous studies, five cell lines did not express Rb protein. None of the cell lines studied retained both tumor suppressor genes in a functional form. The c-myc gene appeared to be intact in all cell lines and copy numbers were close to normal. Northern analysis demonstrated that all cell lines expressed c-myc mRNA but evidence for altered regulation was found in at least two cell lines. Our data suggest that amplification or translocation are not the underlying mechanism for c-myc overexpression in urothelial tumors. No correlation between loss of Rb protein and c-myc expression was observed. The results presented here for the cell lines match well those obtained in vivo. Thus, these cell lines may provide a suitable model for further analysis of molecular alterations in urothelial cancer.     

Clinical significance of p53 mutations in adenocarcinoma of the esophagus and cardia

OBJECTIVE: To compare the frequency and spectrum of p53 gene mutations in adenocarcinomas of the esophagus and cardia and to compare clinical and pathologic features in patients with p53 mutant and nonmutant cancers. SUMMARY BACKGROUND DATA: The p53 gene is commonly mutated in human cancers, and a p53 mutation is reported to be present in more than 50% of esophageal adenocarcinomas. Although many studies have investigated the frequency of p53 protein overexpression in adenocarcinomas of the esophagus or esophagogastric junction, few studies have assessed the frequency and clinical significance of p53 mutations in these tumors. In particular, the prognostic importance of p53 mutation is uncertain. Adenocarcinomas of the esophagus and cardia share many epidemiologic and pathologic features, but it is controversial whether they represent the same tumor. A comparison of the frequency and spectrum of mutations in adenocarcinomas of the esophagus and cardia would test whether these tumors are also similar at the molecular level. METHODS: DNA was isolated from microdissected paraffin-embedded tumor tissues of patients who underwent esophagogastrectomy for adenocarcinoma of the esophagus (n = 19), cardia (esophagogastric junction, n = 12), or subcardia (n = 6). Exons 5 to 8 of the p53 gene were analyzed for the presence of mutations using the polymerase chain reaction with single-strand conformation polymorphism and DNA sequencing of bands showing abnormal mobility. The presence of mutation was confirmed by selective hybridization of a mutant-specific oligonucleotide to DNA isolated from the tumor. RESULTS: p53 mutations were identified in 18 of 37 (48.6%) tumors. Patients with p53 mutant tumors were significantly younger and had a significantly poorer prognosis. There was a similar prevalence of p53 mutations in adenocarcinomas of the esophagus (53%) and cardia (58%). In contrast, mutations were relatively uncommon in subcardia adenocarcinomas (one mutant tumor [17%]). The types of mutations found in the esophageal and the cardia cancers were also similar. CONCLUSIONS: Adenocarcinomas of the esophagus and cardia have a similar frequency and spectrum of p53 gene mutations, suggesting that these tumors have a common pathogenesis. Patients with mutations are younger, have signs of more advanced disease, and have a poorer prognosis than patients without mutations.     

Clinical implications of p53 tumor suppressor gene mutation and protein expression in esophageal adenocarcinomas: results of a ten-year prospective study

OBJECTIVE: This study was undertaken to characterize the spectrum of p53 alterations (mutations and protein expression) in surgically resected esophageal adenocarcinomas, and to correlate molecular alterations with clinicopathologic findings and outcome. METHODS: Between 1991 and 2001, 91 consecutive patients with esophageal adenocarcinomas underwent subtotal esophagectomy. No patient received induction therapy. Strict clinicopathologic criteria were used to define primary esophageal adenocarcinomas. Genomic DNA was extracted from esophageal tumors, each matched with histologically normal esophageal epithelium (internal control) from the resection margin. Polymerase chain reaction was used to amplify p53 exons 4 through 10. Mutations were studied by single-strand conformation polymorphism analysis and direct DNA sequencing. Immunohistochemical testing (monoclonal antibody DO7) was used to evaluate p53 protein distribution. RESULTS: Five-year overall survival was 27.3%. No p53 alterations (mutations and/or protein overexpression) were found in normal esophageal epithelium. A total of 57.1% (n = 52) of tumors had p53 alterations (mutations and/or protein overexpression), which on univariate analysis were associated with poor tumor differentiation (P =.001), advanced pTNM stage (P =.009), and number of involved lymph nodes (0, 1-3, >3; P =.04). Patients with p53 alterations had significantly reduced 5-year overall survival relative to patients with wild-type p53 (15% vs 46%; P =.004). The p53 mutations were predominantly G:C to A:T transitions at CpG dinucleotides (52.2%, 24/46) CONCLUSIONS: We conclude that p53 alterations (mutations and/or protein overexpression) are a predictor of reduced postoperative survival after surgical resection of esophageal adenocarcinomas and that p53 may be a clinically useful molecular marker for stratifying patients in future clinical trials. Patterns of p53 mutations suggest endogenous mutational mechanisms.     

Evaluation of p53 nuclear accumulation in low- and high-grade (WHO/ISUP classification) transitional papillary carcinomas of the bladder for tumor recurrence and progression

OBJECTIVES: To evaluate the association of p53 nuclear accumulation with recurrence and progression in transitional cell carcinomas of the bladder and to examine the distribution of p53 in low-grade and high-grade transitional cell carcinomas according to the World Health Organization/International Society of Urological Pathology classification. PATIENTS AND METHODS: Nuclear accumulations of p53 were examined in a total of 99 patients with transitional cell carcinoma between May 1995 and October 1999. The mean age was 64 years. There were 94 (95%) men and 5 (5%) women. Following resection, surgical specimens were examined, and p53 accumulation with a 20% cutoff value was accepted as positive staining. Of the 99 patients, 52 (53%) had histologically superficial bladder tumors, and 47 (47%) had invasive tumors. Data concerning grade, stage, number of recurrences, and disease progression were available for each patient. RESULTS: The median follow-up period was 55 months. 60 of the 99 patients (61%) had p53 overexpression. The difference for p53 overexpression between low-grade and high-grade tumors was significant (p < 0.05). In low- and high-grade tumors, there was no significant relationship for recurrence between p53-positive and p53-negative groups. But there was a statistically significant relationship between progression and histological grade of the tumors. p53 had no significant relationship with tumor recurrences (p > 0.05), but its relationship with progression was statistically significant (p < 0.05). CONCLUSIONS: We did not find a correlation between tumor recurrence and p53 overexpression, but p53 overexpression has a predictive value in determining tumor progression. High-grade tumors had higher p53-positive values than low-grade tumors. This group of patients should be considered for radical therapies on the basis of other prognostic parameters.     

Numeric Aberration of Chromosome 17 Is Strongly Correlated with p53 Overexpression, Tumor Proliferation and Histopathology in Human Bladder Cancer

Background This study investigated the relationships between the numeric aberrations of chromosome 17 and p53 expression, the proliferating cell nuclear antigen labeling index (PCNA-LI) and histopathology, to determine their prognostic significance in bladder cancer.
Methods Using in situ hybridization (1SH) with a biotin-labeled chromosome-specific DNA probe, the copy number of pericentromeric sequences in chromosome 17 were detected within interphase nuclei in formalin-fixed paraffin-embedded sections from 59 nonmetastasized transitional cell carcinomas (TCCs) of the urinary bladder. Expression of p53 and PCNA-LI were determined in serial sections by an immunohistochemical method.
Results The percentage of hyperdiploid cells for chromosome 17 correlated with p53 overexpression (P< 0.002), PCNA-LI (P< 0.002), increasing tumor grade (P< 0.002) and advanced pathologic stage (P< 0.002). The average percentage of hyperdiploid cells was lower in tumors with negative p53 expression than in tumors with p53 overexpression (P< 0.002). Also, more polysomic TCCs were found in muscle-invasive than in superficial cases (P< 0.01), and there was a difference in both p53 overexpression or PCNA-LI between disomic and polysomic TCCs (P<0.01). Patients with chromosome 17 disomic tumors showed less frequent tumor progression than patients with polysomic tumors (P< 0.05). However, chromosome 17 polysomy was an independent prognostic indicator only for patient survival (P< 0.05).
Conclusion The occurrence and extent of numeric aberrations of chromosome 17 may be associated with the evolution of aggressive growth in TCC and may be a useful indicator for survival.     

Relation between p53 overexpression and established prognostic factors in breast cancer.

The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In breast carcinoma overexpression of p53 is associated with point mutations within highly conserved regions of the p53 gene. These altered genes encode stable p53 proteins that can be detected by standard immunohistochemical techniques unable to detect rapidly degraded wild-type protein. The level of p53 expression in 184 primary breast cancer specimens was assessed by immunohistochemical analysis and related to the following established prognostic factors for breast cancer: age, stage, metastatic involvement, concentration of estrogen and progesterone receptors, proliferative index, and HER-2/neu overexpression. Fifty (27%) of these primary breast cancer specimens had widespread overexpression of p53. Highly significant associations were found between p53 overexpression and late stage, metastatic spread, and low concentration of progesterone receptors. The presence of elevated levels of mutant p53 may itself be a prognostic factor in human breast cancer and activation of this oncogene may be important in the ability of a tumor to metastasize.     

Prospective evaluation of p53 as a prognostic marker in T1 transitional cell carcinoma of the bladder

OBJECTIVE: To prospectively evaluate p53 overexpression as a predictor of survival in patients with a first diagnosis of T1 transitional cell carcinoma (TCC) of the bladder, as several reports implicate p53 as an important prognostic marker for progression and survival, but all previous studies were retrospective, giving conflicting and irreproducible results, rendering inappropriate any attempt at integrating p53 into clinical decision-making. PATIENTS AND METHODS: Patients with a first diagnosis of T1 TCC of the bladder were enrolled; p53 overexpression was assessed by immunohistochemistry (IHC) using both monoclonal antibody 1801 and DO7. The pathological stage and IHC score were assigned by one pathologist, and the markers were scored categorically. RESULTS: Of the 89 patients who were evaluable, 53 had p53-positive tumours. The median follow-up for the survivors was 52 months. Eighty-two patients had high-grade tumours, using the World Health Organisation/International Society of Urological Pathology 1998 grading system. Fifty-eight patients had unifocal tumours and 34 had associated carcinoma in situ. The 3 year and 5 year overall survival rates were 81% (95% Cl: 73%, 90%) and 68% (95% Cl: 56%, 80%) respectively. The 3 year and 5 year disease specific survival rates were 87% (95% Cl: 79%, 94%) and 79% (95% Cl: 70%, 89%) respectively. There was no difference in disease-specific survival between patients with and without p53 over expression (p=0.56) [corrected] CONCLUSIONS: p53 tissue typing by IHC in a prospective cohort of patients with T1 bladder cancer was not clinically useful as a prognostic marker in a contemporary series of T1 tumours.     

The relationships among DNA ploidy type determined by laser scanning cytometry, the overexpression of p53 protein and the numerical aberrations of chromosome 7 in bladder cancer

The cellular DNA content of certain malignancies is regarded as a prognostic parameter. The mutant p53 is thought to destabilize centrosome replication, which leads to aberrant mitosis and chromosome instability. We investigated the relationship among DNA ploidy pattern type, numerical aberrations of chromosome 7 and p53 overexpression in 20 transitional cell carcinomas of the urinary bladder. The DNA ploidy pattern type was determined by laser scanning cytometry, while p53 overexpression was investigated immunohistochemically. Using fluorescence in situ hybridization with chromosome-specific probes, the copy number of chromosome 7 was counted by touch preparations of interphase nuclei. The cytometric analysis revealed that the DNA patterns were highly correlated with both the numerical aberrations of chromosome 7 (p = 0.0002) and the overexpression of p53. The incidences of p53 overexpression in DNA aneuploid tumors and DNA diploid ones were 78% and 10%, respectively (p = 0.0017). Our results suggest that the overexpression of abnormal p53 protein induces DNA aneuploidy in bladder cancer.